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Nuclear and genome dynamics underlying DNA double-strand break repair

Nature Reviews Molecular Cell Biology volume 26, pages 538–557 (2025)Cite this article

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Abstract

Changes in nuclear shape and in the spatial organization of chromosomes in the nucleus commonly occur in cancer, ageing and other clinical contexts that are characterized by increased DNA damage. However, the relationship between nuclear architecture, genome organization, chromosome stability and health remains poorly defined. Studies exploring the connections between the positioning and mobility of damaged DNA relative to various nuclear structures and genomic loci have revealed nuclear and cytoplasmic processes that affect chromosome stability. In this Review, we discuss the dynamic mechanisms that regulate nuclear and genome organization to promote DNA double-strand break (DSB) repair, genome stability and cell survival. Genome dynamics that support DSB repair rely on chromatin states, repair-protein condensates, nuclear or cytoplasmic microtubules and actin filaments, kinesin or myosin motor proteins, the nuclear envelope, various nuclear compartments, chromosome topology, chromatin loop extrusion and diverse signalling cues. These processes are commonly altered in cancer and during natural or premature ageing. Indeed, the reshaping of the genome in nuclear space during DSB repair points to new avenues for therapeutic interventions that may take advantage of new cancer cell vulnerabilities or aim to reverse age-associated defects.

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Fig. 1: Principles of nuclear and genome organization relevant to DSB repair.
Fig. 2: DSB positioning, mobility and repair.
Fig. 3: Molecular mechanisms underlying DSB mobility for repair.
Fig. 4: Roles of genome organization and compartmentalization in DSB repair.
Fig. 5: Chromosome topology and phase separation cooperate to stabilize DNA repair compartments.
Fig. 6: Integrated view of nuclear and genome organization hallmarks underlying DSB repair.

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References

  1. Buchwalter, A., Kaneshiro, J. M. & Hetzer, M. W. Coaching from the sidelines: the nuclear periphery in genome regulation. Nat. Rev. Genet. 20, 39–50 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Mekhail, K., Seebacher, J., Gygi, S. P. & Moazed, D. Role for perinuclear chromosome tethering in maintenance of genome stability. Nature 456, 667–670 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Shokrollahi, M. & Mekhail, K. Interphase microtubules in nuclear organization and genome maintenance. Trends Cell Biol. 31, 721–731 (2021).

    Article  CAS  PubMed  Google Scholar 

  4. Sabari, B. R., Dall’Agnese, A. & Young, R. A. Biomolecular condensates in the nucleus. Trends Biochem. Sci. 45, 961–977 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Guelen, L. et al. Domain organization of human chromosomes revealed by mapping of nuclear lamina interactions. Nature 453, 948–951 (2008).

    Article  CAS  PubMed  Google Scholar 

  6. Zullo, J. M. et al. DNA sequence-dependent compartmentalization and silencing of chromatin at the nuclear lamina. Cell 149, 1474–1487 (2012).

    Article  CAS  PubMed  Google Scholar 

  7. Krenning, L., van den Berg, J. & Medema, R. H. Life or death after a break: what determines the choice? Mol. Cell 76, 346–358 (2019).

    Article  CAS  PubMed  Google Scholar 

  8. Hustedt, N. & Durocher, D. The control of DNA repair by the cell cycle. Nat. Cell Biol. 19, 1–9 (2016).

    Article  PubMed  Google Scholar 

  9. Blackford, A. N. & Jackson, S. P. ATM, ATR, and DNA-PK: the trinity at the heart of the DNA damage response. Mol. Cell 66, 801–817 (2017).

    Article  CAS  PubMed  Google Scholar 

  10. Lisby, M., Mortensen, U. H. & Rothstein, R. Colocalization of multiple DNA double-strand breaks at a single Rad52 repair centre. Nat. Cell Biol. 5, 572–577 (2003).

    Article  CAS  PubMed  Google Scholar 

  11. Aten, J. A. et al. Dynamics of DNA double-strand breaks revealed by clustering of damaged chromosome domains. Science 303, 92–95 (2004).

    Article  CAS  PubMed  Google Scholar 

  12. Oshidari, R. & Mekhail, K. Catch the live show: visualizing damaged DNA in vivo. Methods 142, 24–29 (2018).

    Article  CAS  PubMed  Google Scholar 

  13. Torres-Rosell, J. et al. The Smc5–Smc6 complex and SUMO modification of Rad52 regulates recombinational repair at the ribosomal gene locus. Nat. Cell Biol. 9, 923–931 (2007).

    Article  CAS  PubMed  Google Scholar 

  14. Nagai, S. et al. Functional targeting of DNA damage to a nuclear pore-associated SUMO-dependent ubiquitin ligase. Science 322, 597–602 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Dion, V., Kalck, V., Horigome, C., Towbin, B. D. & Gasser, S. M. Increased mobility of double-strand breaks requires Mec1, Rad9 and the homologous recombination machinery. Nat. Cell Biol. 14, 502–509 (2012).

    Article  CAS  PubMed  Google Scholar 

  16. Mine-Hattab, J. & Rothstein, R. Increased chromosome mobility facilitates homology search during recombination. Nat. Cell Biol. 14, 510–517 (2012).

    Article  CAS  PubMed  Google Scholar 

  17. Ryu, T. et al. Heterochromatic breaks move to the nuclear periphery to continue recombinational repair. Nat. Cell Biol. 17, 1401–1411 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Oshidari, R. et al. Nuclear microtubule filaments mediate non-linear directional motion of chromatin and promote DNA repair. Nat. Commun. 9, 2567 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  19. Krawczyk, P. M. et al. Chromatin mobility is increased at sites of DNA double-strand breaks. J. Cell Sci. 125, 2127–2133 (2012).

    CAS  PubMed  Google Scholar 

  20. Oshidari, R., Mekhail, K. & Seeber, A. Mobility and repair of damaged DNA: random or directed? Trends Cell Biol. 30, 144–156 (2020).

    Article  CAS  PubMed  Google Scholar 

  21. Mine-Hattab, J. & Chiolo, I. Complex chromatin motions for DNA repair. Front. Genet. 11, 800 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Andrews, S. S. Methods for modeling cytoskeletal and DNA filaments. Phys. Biol. 11, 011001 (2014).

    Article  CAS  PubMed  Google Scholar 

  23. Mine-Hattab, J., Recamier, V., Izeddin, I., Rothstein, R. & Darzacq, X. Multi-scale tracking reveals scale-dependent chromatin dynamics after DNA damage. Mol. Biol. Cell 28, 3323–3332 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Hajjoul, H. et al. High-throughput chromatin motion tracking in living yeast reveals the flexibility of the fiber throughout the genome. Genome Res. 23, 1829–1838 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Caridi, C. P. et al. Nuclear F-actin and myosins drive relocalization of heterochromatic breaks. Nature 559, 54–60 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Caridi, C. P. et al. Quantitative methods to investigate the 4D dynamics of heterochromatic repair sites in Drosophila cells. Methods Enzymol. 601, 359–389 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Chiolo, I. et al. Double-strand breaks in heterochromatin move outside of a dynamic HP1a domain to complete recombinational repair. Cell 144, 732–744 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Chung, D. K. et al. Perinuclear tethers license telomeric DSBs for a broad kinesin- and NPC-dependent DNA repair process. Nat. Commun. 6, 7742 (2015).

    Article  CAS  PubMed  Google Scholar 

  29. Lottersberger, F., Karssemeijer, R. A., Dimitrova, N. & de Lange, T. 53BP1 and the LINC complex promote microtubule-dependent DSB mobility and DNA repair. Cell 163, 880–893 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Horigome, C. et al. PolySUMOylation by Siz2 and Mms21 triggers relocation of DNA breaks to nuclear pores through the Slx5/Slx8 STUbL. Genes. Dev. 30, 931–945 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Aymard, F. et al. Genome-wide mapping of long-range contacts unveils clustering of DNA double-strand breaks at damaged active genes. Nat. Struct. Mol. Biol. 24, 353–361 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Schrank, B. R. et al. Nuclear ARP2/3 drives DNA break clustering for homology-directed repair. Nature 559, 61–66 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Zagelbaum, J. et al. Multiscale reorganization of the genome following DNA damage facilitates chromosome translocations via nuclear actin polymerization. Nat. Struct. Mol. Biol. 30, 99–106 (2023).

    Article  CAS  PubMed  Google Scholar 

  34. Arnould, C. et al. Chromatin compartmentalization regulates the response to DNA damage. Nature 623, 183–192 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Therizols, P. et al. Telomere tethering at the nuclear periphery is essential for efficient DNA double strand break repair in subtelomeric region. J. Cell Biol. 172, 189–199 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Palancade, B. et al. Nucleoporins prevent DNA damage accumulation by modulating Ulp1-dependent sumoylation processes. Mol. Biol. Cell 18, 2912–2923 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Chen, B. et al. Transmembrane nuclease NUMEN/ENDOD1 regulates DNA repair pathway choice at the nuclear periphery. Nat. Cell Biol. 25, 1004–1016 (2023).

    Article  CAS  PubMed  Google Scholar 

  38. Shokrollahi, M. et al. DNA double-strand break-capturing nuclear envelope tubules drive DNA repair. Nat. Struct. Mol. Biol. 31, 1319–1330 (2024).

    Article  CAS  PubMed  Google Scholar 

  39. Mekhail, K. & Moazed, D. The nuclear envelope in genome organization, expression and stability. Nat. Rev. Mol. Cell Biol. 11, 317–328 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Strecker, J. et al. DNA damage signalling targets the kinetochore to promote chromatin mobility. Nat. Cell Biol. 18, 281–290 (2016).

    Article  CAS  PubMed  Google Scholar 

  41. Garcia Fernandez, F. et al. Global chromatin mobility induced by a DSB is dictated by chromosomal conformation and defines the HR outcome. eLife 11, e78015 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  42. Capella, M. et al. Nucleolar release of rDNA repeats for repair involves SUMO-mediated untethering by the Cdc48/p97 segregase. Nat. Commun. 12, 4918 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Lawrimore, J. et al. Microtubule dynamics drive enhanced chromatin motion and mobilize telomeres in response to DNA damage. Mol. Biol. Cell 28, 1701–1711 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Neumann, F. R. et al. Targeted INO80 enhances subnuclear chromatin movement and ectopic homologous recombination. Genes. Dev. 26, 369–383 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Seeber, A., Dion, V. & Gasser, S. M. Checkpoint kinases and the INO80 nucleosome remodeling complex enhance global chromatin mobility in response to DNA damage. Genes. Dev. 27, 1999–2008 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Hauer, M. H. et al. Histone degradation in response to DNA damage enhances chromatin dynamics and recombination rates. Nat. Struct. Mol. Biol. 24, 99–107 (2017).

    Article  CAS  PubMed  Google Scholar 

  47. Cheblal, A. et al. DNA damage-induced nucleosome depletion enhances homology search independently of local break movement. Mol. Cell 80, 311–326 (2020).

    Article  CAS  PubMed  Google Scholar 

  48. Zidovska, A., Weitz, D. A. & Mitchison, T. J. Micron-scale coherence in interphase chromatin dynamics. Proc. Natl Acad. Sci. USA 110, 15555–15560 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Meschichi, A. et al. The plant-specific DDR factor SOG1 increases chromatin mobility in response to DNA damage. EMBO Rep. 23, e54736 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. van Attikum, H., Fritsch, O. & Gasser, S. M. Distinct roles for SWR1 and INO80 chromatin remodeling complexes at chromosomal double-strand breaks. EMBO J. 26, 4113–4125 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  51. Horigome, C. et al. SWR1 and INO80 chromatin remodelers contribute to DNA double-strand break perinuclear anchorage site choice. Mol. Cell 55, 626–639 (2014).

    Article  CAS  PubMed  Google Scholar 

  52. Apte, M. S., Masuda, H., Wheeler, D. L. & Cooper, J. P. RNAi and Ino80 complex control rate limiting translocation step that moves rDNA to eroding telomeres. Nucleic Acids Res. 49, 8161–8176 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Jain, D., Hebden, A. K., Nakamura, T. M., Miller, K. M. & Cooper, J. P. HAATI survivors replace canonical telomeres with blocks of generic heterochromatin. Nature 467, 223–227 (2010).

    Article  CAS  PubMed  Google Scholar 

  54. Herbert, S. et al. Chromatin stiffening underlies enhanced locus mobility after DNA damage in budding yeast. EMBO J. 36, 2595–2608 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Liu, S. et al. In vivo tracking of functionally tagged Rad51 unveils a robust strategy of homology search. Nat. Struct. Mol. Biol. 30, 1582–1591 (2023).

    Article  CAS  PubMed  Google Scholar 

  56. Carre-Simon, A. et al. Smc5/6 association with microtubules controls dynamic pericentromeric chromatin folding. Preprint at bioRxiv https://doi.org/10.1101/2024.11.13.623393 (2024).

  57. Kalocsay, M., Hiller, N. J. & Jentsch, S. Chromosome-wide Rad51 spreading and SUMO-H2A.Z-dependent chromosome fixation in response to a persistent DNA double-strand break. Mol. Cell 33, 335–343 (2009).

    Article  CAS  PubMed  Google Scholar 

  58. Cho, N. W., Dilley, R. L., Lampson, M. A. & Greenberg, R. A. Interchromosomal homology searches drive directional ALT telomere movement and synapsis. Cell 159, 108–121 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Dilley, R. L. et al. Break-induced telomere synthesis underlies alternative telomere maintenance. Nature 539, 54–58 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Lezaja, A. & Altmeyer, M. Dealing with DNA lesions: when one cell cycle is not enough. Curr. Opin. Cell Biol. 70, 27–36 (2021).

    Article  CAS  PubMed  Google Scholar 

  61. Lezaja, A. et al. RPA shields inherited DNA lesions for post-mitotic DNA synthesis. Nat. Commun. 12, 3827 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Merigliano, C. & Chiolo, I. Multi-scale dynamics of heterochromatin repair. Curr. Opin. Genet. Dev. 71, 206–215 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Feric, M. et al. Coexisting liquid phases underlie nucleolar subcompartments. Cell 165, 1686–1697 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Wang, M. et al. Stress-induced low complexity RNA activates physiological amyloidogenesis. Cell Rep. 24, 1713–1721 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Hult, C. et al. Enrichment of dynamic chromosomal crosslinks drive phase separation of the nucleolus. Nucleic Acids Res. 45, 11159–11173 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Abraham, K. J. et al. Nucleolar RNA polymerase II drives ribosome biogenesis. Nature 585, 298–302 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Lawrimore, J. et al. The rDNA is biomolecular condensate formed by polymer-polymer phase separation and is sequestered in the nucleolus by transcription and R-loops. Nucleic Acids Res. 49, 4586–4598 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Mostofa, M. G. et al. rDNA condensation promotes rDNA separation from nucleolar proteins degraded for nucleophagy after TORC1 inactivation. Cell Rep. 28, 3423–3434 (2019).

    Article  CAS  PubMed  Google Scholar 

  69. Takeichi, Y., Takuma, T., Ohara, K., Tasnin, M. N. & Ushimaru, T. Interphase chromosome condensation in nutrient-starved conditions requires Cdc14 and Hmo1, but not condensin, in yeast. Biochem. Biophys. Res. Commun. 611, 46–52 (2022).

    Article  CAS  PubMed  Google Scholar 

  70. Mostofa, M. G. et al. CLIP and cohibin separate rDNA from nucleolar proteins destined for degradation by nucleophagy. J. Cell Biol. 217, 2675–2690 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Feng, Z. et al. Rad52 inactivation is synthetically lethal with BRCA2 deficiency. Proc. Natl Acad. Sci. USA 108, 686–691 (2011).

    Article  CAS  PubMed  Google Scholar 

  72. Liang, C. C. et al. Mechanism of single-stranded DNA annealing by RAD52–RPA complex. Nature 629, 697–703 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Chan, J. N. et al. Perinuclear cohibin complexes maintain replicative life span via roles at distinct silent chromatin domains. Dev. Cell 20, 867–879 (2011).

    Article  CAS  PubMed  Google Scholar 

  74. Gutierrez, J. I. & Tyler, J. K. A mortality timer based on nucleolar size triggers nucleolar integrity loss and catastrophic genomic instability. Nat. Aging 4, 1782–1793 (2024).

    Article  PubMed  PubMed Central  Google Scholar 

  75. Sacher, M., Pfander, B., Hoege, C. & Jentsch, S. Control of Rad52 recombination activity by double-strand break-induced SUMO modification. Nat. Cell Biol. 8, 1284–1290 (2006).

    Article  CAS  PubMed  Google Scholar 

  76. Horigome, C., Unozawa, E., Ooki, T. & Kobayashi, T. Ribosomal RNA gene repeats associate with the nuclear pore complex for maintenance after DNA damage. PLoS Genet. 15, e1008103 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Harding, S. M., Boiarsky, J. A. & Greenberg, R. A. ATM dependent silencing links nucleolar chromatin reorganization to DNA damage recognition. Cell Rep. 13, 251–259 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. van Sluis, M. & McStay, B. A localized nucleolar DNA damage response facilitates recruitment of the homology-directed repair machinery independent of cell cycle stage. Genes. Dev. 29, 1151–1163 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  79. Warmerdam, D. O., van den Berg, J. & Medema, R. H. Breaks in the 45S rDNA lead to recombination-mediated loss of repeats. Cell Rep. 14, 2519–2527 (2016).

    Article  CAS  PubMed  Google Scholar 

  80. Korsholm, L. M. et al. Double-strand breaks in ribosomal RNA genes activate a distinct signaling and chromatin response to facilitate nucleolar restructuring and repair. Nucleic Acids Res. 47, 8019–8035 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Marnef, A. et al. A cohesin/HUSH- and LINC-dependent pathway controls ribosomal DNA double-strand break repair. Genes. Dev. 33, 1175–1190 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Mooser, C. et al. Treacle controls the nucleolar response to rDNA breaks via TOPBP1 recruitment and ATR activation. Nat. Commun. 11, 123 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Korsholm, L. M. et al. Recent advances in the nucleolar responses to DNA double-strand breaks. Nucleic Acids Res. 48, 9449–9461 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Kruhlak, M. et al. The ATM repair pathway inhibits RNA polymerase I transcription in response to chromosome breaks. Nature 447, 730–734 (2007).

    Article  CAS  PubMed  Google Scholar 

  85. Larsen, D. H. et al. The NBS1-Treacle complex controls ribosomal RNA transcription in response to DNA damage. Nat. Cell Biol. 16, 792–803 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Pefani, D. E., Tognoli, M. L., Pirincci Ercan, D., Gorgoulis, V. & O’Neill, E. MST2 kinase suppresses rDNA transcription in response to DNA damage by phosphorylating nucleolar histone H2B. EMBO J. 37, e98760 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  87. Fages, J. et al. JMJD6 participates in the maintenance of ribosomal DNA integrity in response to DNA damage. PLoS Genet. 16, e1008511 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Oza, P., Jaspersen, S. L., Miele, A., Dekker, J. & Peterson, C. L. Mechanisms that regulate localization of a DNA double-strand break to the nuclear periphery. Genes. Dev. 23, 912–927 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Loeillet, S. et al. Genetic network interactions among replication, repair and nuclear pore deficiencies in yeast. DNA Repair. 4, 459–468 (2005).

    Article  CAS  PubMed  Google Scholar 

  90. Jaspersen, S. L. et al. The Sad1-UNC-84 homology domain in Mps3 interacts with Mps2 to connect the spindle pole body with the nuclear envelope. J. Cell Biol. 174, 665–675 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Fan, J., Jin, H., Koch, B. A. & Yu, H. G. Mps2 links Csm4 and Mps3 to form a telomere-associated LINC complex in budding yeast. Life Sci. Alliance https://doi.org/10.26508/lsa.202000824 (2020).

  92. Fan, J., Sun, Z. & Wang, Y. The assembly of a noncanonical LINC complex in Saccharomyces cerevisiae. Curr. Genet. 68, 91–96 (2022).

    Article  CAS  PubMed  Google Scholar 

  93. Su, X. A., Dion, V., Gasser, S. M. & Freudenreich, C. H. Regulation of recombination at yeast nuclear pores controls repair and triplet repeat stability. Genes. Dev. 29, 1006–1017 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Kramarz, K. et al. The nuclear pore primes recombination-dependent DNA synthesis at arrested forks by promoting SUMO removal. Nat. Commun. 11, 5643 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Schirmeisen, K. et al. SUMO protease and proteasome recruitment at the nuclear periphery differently affect replication dynamics at arrested forks. Nucleic Acids Res. 52, 8286–8302 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Khadaroo, B. et al. The DNA damage response at eroded telomeres and tethering to the nuclear pore complex. Nat. Cell Biol. 11, 980–987 (2009).

    Article  CAS  PubMed  Google Scholar 

  97. Churikov, D. et al. SUMO-dependent relocalization of eroded telomeres to nuclear pore complexes controls telomere recombination. Cell Rep. 15, 1242–1253 (2016).

    Article  CAS  PubMed  Google Scholar 

  98. Whalen, J. M., Dhingra, N., Wei, L., Zhao, X. & Freudenreich, C. H. Relocation of collapsed forks to the nuclear pore complex depends on sumoylation of DNA repair proteins and permits Rad51 association. Cell Rep. 31, 107635 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Maclay, T., Whalen, J., Johnson, M. & Freudenreich, C. H. The DNA replication checkpoint targets the kinetochore for relocation of collapsed forks to the nuclear periphery. Preprint at bioRxiv https://doi.org/10.1101/2024.06.17.599319 (2024).

  100. Luessing, J. et al. The nuclear kinesin KIF18B promotes 53BP1-mediated DNA double-strand break repair. Cell Rep. 35, 109306 (2021).

    Article  CAS  PubMed  Google Scholar 

  101. Zhu, S. et al. Kinesin Kif2C in regulation of DNA double strand break dynamics and repair. eLife 9, e53402 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  102. Ayoub, N., Jeyasekharan, A. D., Bernal, J. A. & Venkitaraman, A. R. HP1-β mobilization promotes chromatin changes that initiate the DNA damage response. Nature 453, 682–686 (2008).

    Article  CAS  PubMed  Google Scholar 

  103. Goodarzi, A. A. et al. ATM signaling facilitates repair of DNA double-strand breaks associated with heterochromatin. Mol. Cell 31, 167–177 (2008).

    Article  CAS  PubMed  Google Scholar 

  104. Janssen, A., Colmenares, S. U., Lee, T. & Karpen, G. H. Timely double-strand break repair and pathway choice in pericentromeric heterochromatin depend on the histone demethylase dKDM4A. Genes. Dev. 33, 103–115 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Kendek, A. et al. DNA double-strand break movement in heterochromatin depends on the histone acetyltransferase dGcn5. Nucleic Acids Res. 52, 11753–11767 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Colmenares, S. U. et al. Drosophila histone demethylase KDM4A has enzymatic and non-enzymatic roles in controlling heterochromatin integrity. Dev. Cell 42, 156–169 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Caridi, C. P., Plessner, M., Grosse, R. & Chiolo, I. Nuclear actin filaments in DNA repair dynamics. Nat. Cell Biol. 21, 1068–1077 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Ryu, T., Merigliano, C. & Chiolo, I. Nup153 is not required for anchoring heterochromatic DSBs to the nuclear periphery. MicroPubl. Biol. https://doi.org/10.17912/micropub.biology.001176 (2024).

  109. Ryu, T., Bonner, M. R. & Chiolo, I. Cervantes and Quijote protect heterochromatin from aberrant recombination and lead the way to the nuclear periphery. Nucleus 7, 485–497 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  110. Merigliano, C. et al. ‘Off-pore’ nucleoporins relocalize heterochromatic breaks through phase separation. Preprint at bioRxiv https://doi.org/10.1101/2023.12.07.570729 (2023).

  111. Dialynas, G., Delabaere, L. & Chiolo, I. Arp2/3 and Unc45 maintain heterochromatin stability in Drosophila polytene chromosomes. Exp. Biol. Med. 244, 1362–1371 (2019).

    Article  CAS  Google Scholar 

  112. Chiolo, I., Tang, J., Georgescu, W. & Costes, S. V. Nuclear dynamics of radiation-induced foci in euchromatin and heterochromatin. Mutat. Res. 750, 56–66 (2013).

    Article  CAS  PubMed  Google Scholar 

  113. Tsouroula, K. et al. Temporal and spatial uncoupling of DNA double strand break repair pathways within mammalian heterochromatin. Mol. Cell 63, 293–305 (2016).

    Article  CAS  PubMed  Google Scholar 

  114. Jakob, B. et al. DNA double-strand breaks in heterochromatin elicit fast repair protein recruitment, histone H2AX phosphorylation and relocation to euchromatin. Nucleic Acids Res. 39, 6489–6499 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Belin, B. J., Lee, T. & Mullins, R. D. DNA damage induces nuclear actin filament assembly by Formin -2 and Spire-1/2 that promotes efficient DNA repair. eLife 4, e07735 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  116. Palumbieri, M. D. et al. Nuclear actin polymerization rapidly mediates replication fork remodeling upon stress by limiting PrimPol activity. Nat. Commun. 14, 7819 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Lamm, N. et al. Nuclear F-actin counteracts nuclear deformation and promotes fork repair during replication stress. Nat. Cell Biol. 22, 1460–1470 (2020).

    Article  CAS  PubMed  Google Scholar 

  118. Merigliano, C., Palumbieri, M. D., Lopes, M. & Chiolo, I. Replication forks associated with long nuclear actin filaments in mild stress conditions display increased dynamics. MicroPubl. Biol. https://doi.org/10.17912/micropub.biology.001259 (2024).

  119. Nieminuszczy, J. et al. Actin nucleators safeguard replication forks by limiting nascent strand degradation. Nucleic Acids Res. 51, 6337–6354 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Pinzaru, A. M. et al. Replication stress conferred by POT1 dysfunction promotes telomere relocalization to the nuclear pore. Genes. Dev. 34, 1619–1636 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Mitrentsi, I. et al. Heterochromatic repeat clustering imposes a physical barrier on homologous recombination to prevent chromosomal translocations. Mol. Cell 82, 2132–2147 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Soutoglou, E. et al. Positional stability of single double-strand breaks in mammalian cells. Nat. Cell Biol. 9, 675–682 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Jakob, B., Splinter, J., Durante, M. & Taucher-Scholz, G. Live cell microscopy analysis of radiation-induced DNA double-strand break motion. Proc. Natl Acad. Sci. USA 106, 3172–3177 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Roukos, V. et al. Spatial dynamics of chromosome translocations in living cells. Science 341, 660–664 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Le Bozec, B. et al. Circadian PERIOD proteins regulate TC-DSB repair through anchoring to the nuclear envelope. Preprint at bioRxiv https://doi.org/10.1101/2023.05.11.540338 (2024).

  126. Hundal, A., Urman, D., Stanic, M., Hakem, R. & Mekhail, K. Protocol for machine-learning-based 3D image analysis of nuclear envelope tubules in cultured cells. Star. Protoc. 5, 103214 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Lemaitre, C. et al. Nuclear position dictates DNA repair pathway choice. Genes. Dev. 28, 2450–2463 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  128. Ovejero, S. et al. A sterol-PI(4)P exchanger modulates the Tel1/ATM axis of the DNA damage response. EMBO J. 42, e112684 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Portran, D., Schaedel, L., Xu, Z., Thery, M. & Nachury, M. V. Tubulin acetylation protects long-lived microtubules against mechanical ageing. Nat. Cell Biol. 19, 391–398 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Xu, Z. et al. Microtubules acquire resistance from mechanical breakage through intralumenal acetylation. Science 356, 328–332 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Reed, N. A. et al. Microtubule acetylation promotes kinesin-1 binding and transport. Curr. Biol. 16, 2166–2172 (2006).

    Article  CAS  PubMed  Google Scholar 

  132. Ryu, N. M. & Kim, J. M. The role of the α-tubulin acetyltransferase αTAT1 in the DNA damage response. J. Cell Sci. https://doi.org/10.1242/jcs.246702 (2020).

  133. Kumar, A. et al. ATR mediates a checkpoint at the nuclear envelope in response to mechanical stress. Cell 158, 633–646 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Bastianello, G. et al. Cell stretching activates an ATM mechano-transduction pathway that remodels cytoskeleton and chromatin. Cell Rep. 42, 113555 (2023).

    Article  CAS  PubMed  Google Scholar 

  135. Kidiyoor, G. R. et al. ATR is essential for preservation of cell mechanics and nuclear integrity during interstitial migration. Nat. Commun. 11, 4828 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Kovacs, M. T. et al. DNA damage induces nuclear envelope rupture through ATR-mediated phosphorylation of lamin A/C. Mol. Cell 83, 3659–3668 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Joo, Y. K. et al. ATR promotes clearance of damaged DNA and damaged cells by rupturing micronuclei. Mol. Cell 83, 3642–3658 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Harding, S. M. et al. Mitotic progression following DNA damage enables pattern recognition within micronuclei. Nature 548, 466–470 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Mackenzie, K. J. et al. cGAS surveillance of micronuclei links genome instability to innate immunity. Nature 548, 461–465 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Takaki, T., Millar, R., Hiley, C. T. & Boulton, S. J. Micronuclei induced by radiation, replication stress, or chromosome segregation errors do not activate cGAS-STING. Mol. Cell https://doi.org/10.1016/j.molcel.2024.04.017 (2024).

    Article  PubMed  Google Scholar 

  141. Volkman, H. E., Cambier, S., Gray, E. E. & Stetson, D. B. Tight nuclear tethering of cGAS is essential for preventing autoreactivity. eLife 8, e47491 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Boyer, J. A. et al. Structural basis of nucleosome-dependent cGAS inhibition. Science 370, 450–454 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Kujirai, T. et al. Structural basis for the inhibition of cGAS by nucleosomes. Science 370, 455–458 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Michalski, S. et al. Structural basis for sequestration and autoinhibition of cGAS by chromatin. Nature 587, 678–682 (2020).

    Article  CAS  PubMed  Google Scholar 

  145. Pathare, G. R. et al. Structural mechanism of cGAS inhibition by the nucleosome. Nature 587, 668–672 (2020).

    Article  CAS  PubMed  Google Scholar 

  146. Zhao, B. et al. The molecular basis of tight nuclear tethering and inactivation of cGAS. Nature 587, 673–677 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Martin, S. et al. A p62-dependent rheostat dictates micronuclei catastrophe and chromosome rearrangements. Science 385, eadj7446 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Di Bona, M. et al. Micronuclear collapse from oxidative damage. Science 385, eadj8691 (2024).

    Article  PubMed  PubMed Central  Google Scholar 

  149. Dekker, C., Haering, C. H., Peters, J. M. & Rowland, B. D. How do molecular motors fold the genome? Science 382, 646–648 (2023).

    Article  CAS  PubMed  Google Scholar 

  150. Gabriele, M. et al. Dynamics of CTCF- and cohesin-mediated chromatin looping revealed by live-cell imaging. Science 376, 496–501 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Fudenberg, G. et al. Formation of chromosomal domains by loop extrusion. Cell Rep. 15, 2038–2049 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Arnould, C. et al. Loop extrusion as a mechanism for formation of DNA damage repair foci. Nature 590, 660–665 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Piazza, A. et al. Cohesin regulates homology search during recombinational DNA repair. Nat. Cell Biol. 23, 1176–1186 (2021).

    Article  CAS  PubMed  Google Scholar 

  154. Dequeker, B. J. H. et al. MCM complexes are barriers that restrict cohesin-mediated loop extrusion. Nature 606, 197–203 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Jeppsson, K. et al. Cohesin-dependent chromosome loop extrusion is limited by transcription and stalled replication forks. Sci. Adv. 8, eabn7063 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Banigan, E. J. et al. Transcription shapes 3D chromatin organization by interacting with loop extrusion. Proc. Natl Acad. Sci. USA 120, e2210480120 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Brandão, H. B. et al. RNA polymerases as moving barriers to condensin loop extrusion. Proc. Natl Acad. Sci. USA 116, 20489–20499 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  158. Zhang, S., Übelmesser, N., Barbieri, M. & Papantonis, A. Enhancer-promoter contact formation requires RNAPII and antagonizes loop extrusion. Nat. Genet. 55, 832–840 (2023).

    Article  CAS  PubMed  Google Scholar 

  159. Karpinska, M. A. & Oudelaar, A. M. The role of loop extrusion in enhancer-mediated gene activation. Curr. Opin. Genet. Dev. 79, 102022 (2023).

    Article  CAS  PubMed  Google Scholar 

  160. Batty, P. et al. Cohesin-mediated DNA loop extrusion resolves sister chromatids in G2 phase. EMBO J. 42, e113475 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Chan, B. & Rubinstein, M. Activity-driven chromatin organization during interphase: compaction, segregation, and entanglement suppression. Proc. Natl Acad. Sci. USA 121, e2401494121 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Zhang, Y., Zhang, X., Dai, H. Q., Hu, H. & Alt, F. W. The role of chromatin loop extrusion in antibody diversification. Nat. Rev. Immunol. 22, 550–566 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Yang, J. H., Brandão, H. B. & Hansen, A. S. DNA double-strand break end synapsis by DNA loop extrusion. Nat. Commun. 14, 1913 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Emerson, D. J. et al. Cohesin-mediated loop anchors confine the locations of human replication origins. Nature 606, 812–819 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Kim, E., Gonzalez, A. M., Pradhan, B., van der Torre, J. & Dekker, C. Condensin-driven loop extrusion on supercoiled DNA. Nat. Struct. Mol. Biol. 29, 719–727 (2022).

    Article  CAS  PubMed  Google Scholar 

  166. Lieberman-Aiden, E. et al. Comprehensive mapping of long-range interactions reveals folding principles of the human genome. Science 326, 289–293 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Solovei, I., Thanisch, K. & Feodorova, Y. How to rule the nucleus: divide et impera. Curr. Opin. Cell Biol. 40, 47–59 (2016).

    Article  CAS  PubMed  Google Scholar 

  168. Alberti, S. & Hyman, A. A. Biomolecular condensates at the nexus of cellular stress, protein aggregation disease and ageing. Nat. Rev. Mol. Cell Biol. 22, 196–213 (2021).

    Article  CAS  PubMed  Google Scholar 

  169. Hyman, A. A., Weber, C. A. & Julicher, F. Liquid-liquid phase separation in biology. Annu. Rev. Cell Dev. Biol. 30, 39–58 (2014).

    Article  CAS  PubMed  Google Scholar 

  170. Shin, Y. & Brangwynne, C. P. Liquid phase condensation in cell physiology and disease. Science 357, eaaf4382 (2017).

    Article  PubMed  Google Scholar 

  171. Larson, A. G. et al. Liquid droplet formation by HP1α suggests a role for phase separation in heterochromatin. Nature 547, 236–240 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Strom, A. R. et al. Phase separation drives heterochromatin domain formation. Nature 547, 241–245 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. Hildebrand, E. M. & Dekker, J. Mechanisms and functions of chromosome compartmentalization. Trends Biochem. Sci. 45, 385–396 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. Goel, V. Y., Huseyin, M. K. & Hansen, A. S. Region capture micro-C reveals coalescence of enhancers and promoters into nested microcompartments. Nat. Genet. 55, 1048–1056 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. Li, J. & Pertsinidis, A. Nanoscale nuclear environments, fine-scale 3D genome organization and transcription regulation. Curr. Opin. Syst. Biol. https://doi.org/10.1016/j.coisb.2022.100436 (2022).

  176. Iacovoni, J. S. et al. High-resolution profiling of γH2AX around DNA double strand breaks in the mammalian genome. EMBO J. 29, 1446–1457 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  177. Caron, P. et al. Cohesin protects genes against γH2AX induced by DNA double-strand breaks. PLoS Genet. 8, e1002460 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  178. Collins, P. L. et al. DNA double-strand breaks induce H2Ax phosphorylation domains in a contact-dependent manner. Nat. Commun. 11, 3158 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  179. Arnould, C. & Legube, G. The secret life of chromosome loops upon DNA double-strand break. J. Mol. Biol. 432, 724–736 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  180. Phipps, J. & Dubrana, K. DNA repair in space and time: safeguarding the genome with the cohesin complex. Genes https://doi.org/10.3390/genes13020198 (2022).

  181. Peng, X. P. & Zhao, X. The multi-functional Smc5/6 complex in genome protection and disease. Nat. Struct. Mol. Biol. 30, 724–734 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  182. Fu, J. et al. ATM–ESCO2–SMC3 axis promotes 53BP1 recruitment in response to DNA damage and safeguards genome integrity by stabilizing cohesin complex. Nucleic Acids Res. 51, 7376–7391 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  183. Scherzer, M., Giordano, F., Ferran, M. S. & Ström, L. Recruitment of Scc2/4 to double-strand breaks depends on γH2A and DNA end resection. Life Sci. Alliance https://doi.org/10.26508/lsa.202101244 (2022).

  184. Pradhan, B. et al. The Smc5/6 complex is a DNA loop-extruding motor. Nature 616, 843–848 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  185. Kim, S. T., Xu, B. & Kastan, M. B. Involvement of the cohesin protein, Smc1, in Atm-dependent and independent responses to DNA damage. Genes. Dev. 16, 560–570 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  186. van Ruiten, M. S. et al. The cohesin acetylation cycle controls chromatin loop length through a PDS5A brake mechanism. Nat. Struct. Mol. Biol. 29, 586–591 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  187. Bauerschmidt, C. et al. Cohesin phosphorylation and mobility of SMC1 at ionizing radiation-induced DNA double-strand breaks in human cells. Exp. Cell Res. 317, 330–337 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  188. Kim, B. J. et al. Genome-wide reinforcement of cohesin binding at pre-existing cohesin sites in response to ionizing radiation in human cells. J. Biol. Chem. 285, 22784–22792 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  189. Sanders, J. T. et al. Radiation-induced DNA damage and repair effects on 3D genome organization. Nat. Commun. 11, 6178 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  190. Gelot, C. et al. The cohesin complex prevents the end joining of distant DNA double-strand ends. Mol. Cell 61, 15–26 (2016).

    Article  CAS  PubMed  Google Scholar 

  191. Lee, C. S. et al. Chromosome position determines the success of double-strand break repair. Proc. Natl Acad. Sci. USA 113, E146–E154 (2016).

    CAS  PubMed  Google Scholar 

  192. Wang, R. W., Lee, C. S. & Haber, J. E. Position effects influencing intrachromosomal repair of a double-strand break in budding yeast. PLoS ONE 12, e0180994 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  193. Clouaire, T. et al. Comprehensive mapping of histone modifications at DNA double-strand breaks deciphers repair pathway chromatin signatures. Mol. Cell 72, 250–262 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  194. Chapman, J. R., Sossick, A. J., Boulton, S. J. & Jackson, S. P. BRCA1-associated exclusion of 53BP1 from DNA damage sites underlies temporal control of DNA repair. J. Cell Sci. 125, 3529–3534 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  195. Natale, F. et al. Identification of the elementary structural units of the DNA damage response. Nat. Commun. 8, 15760 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  196. Ochs, F. et al. Stabilization of chromatin topology safeguards genome integrity. Nature 574, 571–574 (2019).

    Article  CAS  PubMed  Google Scholar 

  197. Spegg, V. & Altmeyer, M. Biomolecular condensates at sites of DNA damage: more than just a phase. DNA Repair. 106, 103179 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  198. Huang, J. et al. SLFN5-mediated chromatin dynamics sculpt higher-order DNA repair topology. Mol. Cell 83, 1043–1060 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  199. Balasubramanian, S. et al. Protection of nascent DNA at stalled replication forks is mediated by phosphorylation of RIF1 intrinsically disordered region. eLife 11, e75047 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  200. Phipps, J. et al. Cohesin complex oligomerization maintains end-tethering at DNA double-strand breaks. Nat. Cell Biol. https://doi.org/10.1038/s41556-024-01552-2 (2024).

  201. Kilic, S. et al. Phase separation of 53BP1 determines liquid-like behavior of DNA repair compartments. EMBO J. 38, e101379 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  202. Neumaier, T. et al. Evidence for formation of DNA repair centers and dose-response nonlinearity in human cells. Proc. Natl Acad. Sci. USA 109, 443–448 (2012).

    Article  PubMed  Google Scholar 

  203. Zagelbaum, J. & Gautier, J. Double-strand break repair and mis-repair in 3D. DNA Repair https://doi.org/10.1016/j.dnarep.2022.103430 (2023).

  204. Marnef, A. & Legube, G. Organizing DNA repair in the nucleus: DSBs hit the road. Curr. Opin. Cell Biol. 46, 1–8 (2017).

    Article  CAS  PubMed  Google Scholar 

  205. Schrank, B. & Gautier, J. Assembling nuclear domains: lessons from DNA repair. J. Cell Biol. 218, 2444–2455 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  206. Pessina, F. et al. Functional transcription promoters at DNA double-strand breaks mediate RNA-driven phase separation of damage-response factors. Nat. Cell Biol. 21, 1286–1299 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  207. Caron, P. et al. Non-redundant functions of ATM and DNA-PKcs in response to DNA double-strand breaks. Cell Rep. 13, 1598–1609 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  208. Timashev, L. A., Babcock, H., Zhuang, X. & de Lange, T. The DDR at telomeres lacking intact shelterin does not require substantial chromatin decompaction. Genes. Dev. 31, 578–589 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  209. Muzzopappa, F. et al. Detecting and quantifying liquid-liquid phase separation in living cells by model-free calibrated half-bleaching. Nat. Commun. 13, 7787 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  210. Falk, M. et al. Heterochromatin drives compartmentalization of inverted and conventional nuclei. Nature 570, 395–399 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  211. Case, L. B., Zhang, X., Ditlev, J. A. & Rosen, M. K. Stoichiometry controls activity of phase-separated clusters of actin signaling proteins. Science 363, 1093–1097 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  212. Oshidari, R. et al. DNA repair by Rad52 liquid droplets. Nat. Commun. 11, 695 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  213. Alshareedah, I. et al. The human RAD52 complex undergoes phase separation and facilitates bundling and end-to-end tethering of RAD51 presynaptic filaments. Preprint at bioRxiv https://doi.org/10.1101/2024.12.09.627445 (2024).

  214. Spegg, V. & Altmeyer, M. Genome maintenance meets mechanobiology. Chromosoma 133, 15–36 (2024).

    Article  CAS  PubMed  Google Scholar 

  215. Izhar, L. et al. A systematic analysis of factors localized to damaged chromatin reveals PARP-dependent recruitment of transcription factors. Cell Rep. 11, 1486–1500 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  216. Cuella-Martin, R. et al. 53BP1 integrates DNA repair and p53-dependent cell fate decisions via distinct mechanisms. Mol. Cell 64, 51–64 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  217. Ghodke, I. et al. AHNAK controls 53BP1-mediated p53 response by restraining 53BP1 oligomerization and phase separation. Mol. Cell 81, 2596–2610 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  218. Laflamme, G. & Mekhail, K. Biomolecular condensates as arbiters of biochemical reactions inside the nucleus. Commun. Biol. https://doi.org/10.1038/s42003-020-01517-9 (2020).

  219. Altmeyer, M. & Lukas, J. To spread or not to spread-chromatin modifications in response to DNA damage. Curr. Opin. Genet. Dev. 23, 156–165 (2013).

    Article  CAS  PubMed  Google Scholar 

  220. Jungmichel, S. & Stucki, M. MDC1: the art of keeping things in focus. Chromosoma 119, 337–349 (2010).

    Article  CAS  PubMed  Google Scholar 

  221. Feng, L. L. et al. Ubiquitin-induced RNF168 condensation promotes DNA double-strand break repair. Proc. Natl Acad. Sci. USA 121, e2322972121 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  222. Huang, D. & Kraus, W. L. The expanding universe of PARP1-mediated molecular and therapeutic mechanisms. Mol. Cell 82, 2315–2334 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  223. Teloni, F. & Altmeyer, M. Readers of poly(ADP-ribose): designed to be fit for purpose. Nucleic Acids Res. 44, 993–1006 (2016).

    Article  CAS  PubMed  Google Scholar 

  224. Altmeyer, M. et al. Liquid demixing of intrinsically disordered proteins is seeded by poly(ADP-ribose). Nat. Commun. 6, 8088 (2015).

    Article  CAS  PubMed  Google Scholar 

  225. Patel, A. et al. A liquid-to-solid phase transition of the ALS protein FUS accelerated by disease mutation. Cell 162, 1066–1077 (2015).

    Article  CAS  PubMed  Google Scholar 

  226. Aguzzi, A. & Altmeyer, M. Phase separation: linking cellular compartmentalization to disease. Trends Cell Biol. 26, 547–558 (2016).

    Article  CAS  PubMed  Google Scholar 

  227. Harami, G. M. et al. Phase separation by ssDNA binding protein controlled via protein-protein and protein-DNA interactions. Proc. Natl Acad. Sci. USA 117, 26206–26217 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  228. Mine-Hattab, J. et al. Single molecule microscopy reveals key physical features of repair foci in living cells. eLife 10, e60577 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  229. Frattini, C. et al. TopBP1 assembles nuclear condensates to switch on ATR signaling. Mol. Cell 81, 1231–1245 (2021).

    Article  CAS  PubMed  Google Scholar 

  230. Gai, X. C. et al. Pre-ribosomal RNA reorganizes DNA damage repair factors in nucleus during meiotic prophase and DNA damage response. Cell Res. 32, 254–268 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  231. Wang, Y. L. et al. MRNIP condensates promote DNA double-strand break sensing and end resection. Nat. Commun. https://doi.org/10.1038/s41467-022-30303-w (2022).

  232. Qin, C. L. T. et al. RAP80 phase separation at DNA double-strand break promotes BRCA1 recruitment. Nucleic Acids Res. 51, 9733–9747 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  233. Spegg, V. et al. Phase separation properties of RPA combine high-affinity ssDNA binding with dynamic condensate functions at telomeres. Nat. Struct. Mol. Biol. 30, 451–462 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  234. Long, Q. L. et al. The phosphorylated trimeric SOSS1 complex and RNA polymerase II trigger liquid-liquid phase separation at double-strand breaks. Cell Rep. https://doi.org/10.1016/j.celrep.2023.113489 (2023).

  235. Alghoul, E. et al. Compartmentalization of the SUMO/RNF4 pathway by SLX4 drives DNA repair. Mol. Cell 83, 1640–1658 (2023).

    Article  CAS  PubMed  Google Scholar 

  236. Egger, T., Morano, L., Blanchard, M. P., Basbous, J. & Constantinou, A. Spatial organization and functions of Chk1 activation by TopBP1 biomolecular condensates. Cell Rep. 43, 114064 (2024).

    Article  CAS  PubMed  Google Scholar 

  237. Wei, M., Huang, X., Liao, L., Tian, Y. & Zheng, X. SENP1 decreases RNF168 phase separation to promote DNA damage repair and drug resistance in colon cancer. Cancer Res. 83, 2908–2923 (2023).

    Article  CAS  PubMed  Google Scholar 

  238. Badiee, M. et al. Switch-like compaction of poly(ADP-ribose) upon cation binding. Proc. Natl Acad. Sci. USA 120, 945–961 (2023).

    Article  Google Scholar 

  239. Chappidi, N. et al. PARP1-DNA co-condensation drives DNA repair site assembly to prevent disjunction of broken DNA ends. Cell 187, 945–961 (2024).

    Article  CAS  PubMed  Google Scholar 

  240. Levone, B. R. et al. FUS-dependent liquid-liquid phase separation is important for DNA repair initiation. J. Cell Biol. https://doi.org/10.1083/jcb.202008030 (2021).

  241. Mamontova, E. M. et al. FUS RRM regulates poly(ADP-ribose) levels after transcriptional arrest and PARP-1 activation on DNA damage. Cell Rep. 42, 113199 (2023).

    Article  CAS  PubMed  Google Scholar 

  242. Singatulina, A. S. et al. PARP-1 activation directs FUS to DNA damage sites to form PARG-reversible compartments enriched in damaged DNA. Cell Rep. 27, 1809–1821 (2019).

    Article  CAS  PubMed  Google Scholar 

  243. Rhine, K. et al. Poly(ADP-ribose) drives condensation of FUS via a transient interaction. Mol. Cell 82, 969–985 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  244. Vu, D. D. et al. Multivalent interactions of the disordered regions of XLF and XRCC4 foster robust cellular NHEJ and drive the formation of ligation-boosting condensates in vitro. Nat. Struct. Mol. Biol. 31, 1732–1744 (2024).

    Article  CAS  PubMed  Google Scholar 

  245. Nosella, M. L. et al. Poly(ADP-ribosyl)ation enhances nucleosome dynamics and organizes DNA damage repair components within biomolecular condensates. Mol. Cell 84, 429–446 (2024).

    Article  CAS  PubMed  Google Scholar 

  246. Sukhanova, M. V., Anarbaev, R. O., Maltseva, E. A., Pastre, D. & Lavrik, O. I. FUS microphase separation: regulation by nucleic acid polymers and DNA repair proteins. Int. J. Mol. Sci. https://doi.org/10.3390/ijms232113200 (2022).

  247. Chin Sang, C. et al. PARP1 condensates differentially partition DNA repair proteins and enhance DNA ligation. EMBO Rep. 25, 5635–5666 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  248. Nakamura, K. et al. H4K20me0 recognition by BRCA1–BARD1 directs homologous recombination to sister chromatids. Nat. Cell Biol. 21, 311–318 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  249. Saredi, G. et al. H4K20me0 marks post-replicative chromatin and recruits the TONSL–MMS22L DNA repair complex. Nature 534, 714–718 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  250. Pellegrino, S., Michelena, J., Teloni, F., Imhof, R. & Altmeyer, M. Replication-coupled dilution of H4K20me2 guides 53BP1 to pre-replicative chromatin. Cell Rep. 19, 1819–1831 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  251. Michelena, J., Pellegrino, S., Spegg, V. & Altmeyer, M. Replicated chromatin curtails 53BP1 recruitment in BRCA1-proficient and BRCA1-deficient cells. Life Sci. Alliance https://doi.org/10.26508/lsa.202101023 (2021).

  252. Alberti, S. & Dormann, D. Liquid-liquid phase separation in disease. Annu. Rev. Genet. 53, 171–194 (2019).

    Article  CAS  PubMed  Google Scholar 

  253. Alberti, S., Gladfelter, A. & Mittag, T. Considerations and challenges in studying liquid-liquid phase separation and biomolecular condensates. Cell 176, 419–434 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  254. Erdel, F. & Rippe, K. Formation of chromatin subcompartments by phase separation. Biophys. J. 114, 2262–2270 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  255. Mittag, T. & Pappu, R. V. A conceptual framework for understanding phase separation and addressing open questions and challenges. Mol. Cell 82, 2201–2214 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  256. Taylor, A. M. R. et al. Chromosome instability syndromes. Nat. Rev. Dis. Primers 5, 64 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  257. Kubben, N. & Misteli, T. Shared molecular and cellular mechanisms of premature ageing and ageing-associated diseases. Nat. Rev. Mol. Cell Biol. 18, 595–609 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  258. Eriksson, M. et al. Recurrent de novo point mutations in lamin A cause Hutchinson–Gilford progeria syndrome. Nature 423, 293–298 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  259. Liu, B. et al. Genomic instability in laminopathy-based premature aging. Nat. Med. 11, 780–785 (2005).

    Article  CAS  PubMed  Google Scholar 

  260. Liu, G. H. et al. Recapitulation of premature ageing with iPSCs from Hutchinson-Gilford progeria syndrome. Nature 472, 221–225 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  261. Li, H., Vogel, H., Holcomb, V. B., Gu, Y. & Hasty, P. Deletion of Ku70, Ku80, or both causes early aging without substantially increased cancer. Mol. Cell Biol. 27, 8205–8214 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  262. Espejel, S. et al. Shorter telomeres, accelerated ageing and increased lymphoma in DNA-PKcs-deficient mice. EMBO Rep. 5, 503–509 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  263. Zhang, H., Xiong, Z. M. & Cao, K. Mechanisms controlling the smooth muscle cell death in progeria via down-regulation of poly(ADP-ribose) polymerase 1. Proc. Natl Acad. Sci. USA 111, E2261–E2270 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  264. Lutz, R. J., Trujillo, M. A., Denham, K. S., Wenger, L. & Sinensky, M. Nucleoplasmic localization of prelamin A: implications for prenylation-dependent lamin A assembly into the nuclear lamina. Proc. Natl Acad. Sci. USA 89, 3000–3004 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  265. Gordon, L. B. et al. Clinical trial of a farnesyltransferase inhibitor in children with Hutchinson–Gilford progeria syndrome. Proc. Natl Acad. Sci. USA 109, 16666–16671 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  266. Gordon, L. B. et al. Association of lonafarnib treatment vs no treatment with mortality rate in patients with hutchinson-gilford progeria syndrome. JAMA 319, 1687–1695 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  267. Kline, A. D. et al. Diagnosis and management of Cornelia de Lange syndrome: first international consensus statement. Nat. Rev. Genet. 19, 649–666 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  268. Krantz, I. D. et al. Cornelia de Lange syndrome is caused by mutations in NIPBL, the human homolog of Drosophila melanogaster Nipped-B. Nat. Genet. 36, 631–635 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  269. Tonkin, E. T., Wang, T. J., Lisgo, S., Bamshad, M. J. & Strachan, T. NIPBL, encoding a homolog of fungal Scc2-type sister chromatid cohesion proteins and fly Nipped-B, is mutated in Cornelia de Lange syndrome. Nat. Genet. 36, 636–641 (2004).

    Article  CAS  PubMed  Google Scholar 

  270. Musio, A. et al. X-linked Cornelia de Lange syndrome owing to SMC1L1 mutations. Nat. Genet. 38, 528–530 (2006).

    Article  CAS  PubMed  Google Scholar 

  271. Deardorff, M. A. et al. RAD21 mutations cause a human cohesinopathy. Am. J. Hum. Genet. 90, 1014–1027 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  272. Ravenscroft, G. et al. A novel ACTA1 mutation resulting in a severe congenital myopathy with nemaline bodies, intranuclear rods and type I fibre predominance. Neuromuscul. Disord. 21, 31–36 (2011).

    Article  PubMed  Google Scholar 

  273. Riviere, J. B. et al. De novo mutations in the actin genes ACTB and ACTG1 cause Baraitser-Winter syndrome. Nat. Genet. 44, 440–444 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  274. Hirokawa, N., Noda, Y., Tanaka, Y. & Niwa, S. Kinesin superfamily motor proteins and intracellular transport. Nat. Rev. Mol. Cell Biol. 10, 682–696 (2009).

    Article  CAS  PubMed  Google Scholar 

  275. Itai, T. et al. De novo heterozygous variants in KIF5B cause kyphomelic dysplasia. Clin. Genet. 102, 3–11 (2022).

    Article  CAS  PubMed  Google Scholar 

  276. Kalantari, S. & Filges, I. ‘Kinesinopathies’: emerging role of the kinesin family member genes in birth defects. J. Med. Genet. 57, 797–807 (2020).

    Article  CAS  PubMed  Google Scholar 

  277. Marzo, M. G. et al. Molecular basis for dyneinopathies reveals insight into dynein regulation and dysfunction. eLife 8, e47246 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  278. Yildiz, A. Mechanism and regulation of kinesin motors. Nat. Rev. Mol. Cell Biol. https://doi.org/10.1038/s41580-024-00780-6 (2024).

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Acknowledgements

We thank J. N. Y. Chan for comments and assistance with manuscript formatting and C. C. Rawal for comments. We apologise to researchers whose work could not be cited due to space limitations. The Chiolo lab is supported by the NIH (Grants R01GM117376 and R01GM157834) and the National Science Foundation (NSF; Career Grant 1751197). The Altmeyer lab is supported by the Swiss National Science Foundation (Grant 310030_197003). The Legube lab is supported by grants from the European Research Council (ERC-AdG-101019963) and the Association Contre le Cancer (ARC). The Mekhail lab is supported by the Canadian Institutes of Health Research (CIHR; Grants 180469 and 190143) and the Royal Society of Canada.

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Authors and Affiliations

  1. Department of Molecular and Computational Biology, University of Southern California, Los Angeles, CA, USA

    Irene Chiolo

  2. Department of Molecular Mechanisms of Disease, University of Zurich (UZH), Zurich, Switzerland

    Matthias Altmeyer

  3. MCD, Centre de Biologie Intégrative (CBI), CNRS, Université de Toulouse, UT3, Toulouse, France

    Gaëlle Legube

  4. Department of Laboratory Medicine and Pathobiology, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada

    Karim Mekhail

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  1. Irene Chiolo
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  2. Matthias Altmeyer
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  3. Gaëlle Legube
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  4. Karim Mekhail
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The authors contributed equally to all aspects of the article.

Corresponding authors

Correspondence to Irene Chiolo, Matthias Altmeyer, Gaëlle Legube or Karim Mekhail.

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Competing interests

K.M. is listed as an inventor on a patent application (PCT/CA2024/051735) by The Governing Council of the University of Toronto related to the modulation of DNA double-strand break-capturing nuclear envelope tubules. The other authors declare no competing interest.

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Supplementary information

Glossary

Anomalous Rouse diffusion

A type of sub-diffusive motion where a single particle, such as a segment of a DNA polymer, moves slower than expected for normal diffusion owing to physical constraints, including those imposed by polymer entanglement.

Brownian motion

Random movement of particles suspended in a medium, such as a liquid, with no preferential directionality.

Cajal bodies

Nuclear bodies first reported by Santiago Ramón y Cajal in 1903 often associating with the nucleolus and containing RNA processing factors and involved in the biogenesis of small nuclear ribonucleoprotein particles.

DNA repair foci

Microscopically discernible accumulation of DNA repair proteins at sites of DNA damage. Also referred to as ionizing radiation-induced foci (or IRIF) when induced by ionizing radiation.

Loop extrusion

An energy-dependent process carried out by structural maintenance of chromosomes complexes, wherein chromatin is reeled in by a molecular motor and extruded as a loop. Loop extrusion contributes to genome organization and stability.

Nucleolus

Large membrane-less nuclear compartment, where ribosomal (rDNA) is transcribed and ribosome biogenesis occurs. A hotspot of genomic instability owing to the highly repetitive nature of rDNA, which also harbours replication-fork-blocking and double-strand break-inducing elements.

Polycomb bodies

Microscopically discernible accumulation of polycomb group (PcG) proteins in the nucleus, associated with PcG-dependent gene repression.

Promyelocytic leukaemia bodies

Nuclear bodies characterized by the promyelocytic leukaemia (PML) protein and multivalent interactions between SUMOylated proteins and proteins containing SUMO-interacting motifs. PMLs are involved in multiple cellular processes, including in telomere repair.

Super-enhancer

Nuclear cluster of gene enhancers; associated with the accumulation and clustering of transcription factors and coactivators and active histone modifications such as H3K27ac.

Topologically associating domain

Genomic region of ~1 Mb in human cells, in which DNA sequences interact more frequently with each other than with sequences at other genomic regions. Topologically associating domain borders are enriched in CCCTC-binding factor and cohesin binding.

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Chiolo, I., Altmeyer, M., Legube, G. et al. Nuclear and genome dynamics underlying DNA double-strand break repair. Nat Rev Mol Cell Biol 26, 538–557 (2025). https://doi.org/10.1038/s41580-025-00828-1

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