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Protein activity regulated by phosphorylation can result in subcellular relocation. Here, the authors present a high throughput spatial phosphoproteomics approach to profile six subcellular compartments, providing insights into EGFR and stress signalling dynamics.

Two studies identify aldehyde metabolites as a potential endogenous source of ICLs.

Intestinal stem cells are responsible for replenishing cells within the high-turnover intestinal epithelium. Here they show that ribosome dynamics affect intestinal stem cell identity through a mechanism that is triggered by changes in nutrient availability.

Centriolar satellites (CS) dynamically remodel in response to cellular stress. Here the authors describe a mechanism for stress-mediated remodelling, whereby CEP131 is phosphorylated downstream of p38, creating binding sites for 14-3-3 that lead to the sequestration of CEP131 in the cytoplasm and disassembly of CS.

HERC2 regulates the retention of repair proteins 53BP1, RAP80 and BRCA1 on damaged chromosomes in response to ionizing radiation by forming a complex with the ubiquitin ligases RNF8 and RNF168. Hecr2 deficiency leads to radiosensitivity.

Two studies show that the E3 ubiquitin ligase RNF138 is recruited to DNA double-strand break sites, where it ubiquitylates key repair factors to promote DNA-end resection and homologous recombination. These findings add insights into the multilayered regulatory mechanisms underlying DNA double-strand break repair pathway choice in mammalian cells.

The proliferating cell nuclear antigen (PCNA) processivity factor provides a central regulatory platform during DNA replication and associated processes, including DNA damage repair. The interaction of PCNA with many cellular proteins is key to this function and is subject to tight, multilayered control.

Signalling by ubiquitin, SUMO and other ubiquitin-like modifiers (UBLs), and crosstalk between these modifications, underlies cellular responses to DNA double-strand breaks (DSBs). Important insights have been gained into the mechanisms by which ubiquitin and UBLs regulate protein interactions at DSB sites to enable accurate repair in mammalian cells, thereby protecting genome integrity.

Centrosomes drive mitotic spindle formation and chromosome segregation. Here, the authors show that centrosome stability is regulated by selective autophagic degradation of centriolar satellite components in a process they term doryphagy, connecting autophagy and chromosomal integrity.

53BP1 is marker of double-strand breaks and accumulates in nuclear foci. These foci are shown to accumulate in G1 at lesions generated by replication stress and may shield lesions from erosion.

Hansen et al. find that SCAI (suppressor of cancer cell invasion) is a 53BP1-binding protein that acts to repair in heterochromatin and to facilitate meiotic recombination in germ cells.

UV-light-induced DNA damage affects RNA metabolism but the underlying signalling pathways are largely unexplored. Here, the authors show that UV light triggers p38-MK2-mediated phosphorylation of the NELF complex, promoting its release from chromatin and concurrent transcriptional elongation.

The AAA ATPase p97 (VCP) is thought to remove specific proteins from chromatin at sites of DNA damage, to allow proper repair or processing, but how p97 targets those sites was unclear. The protein DVC1 is now shown to localize to sites of replication stress and UV-light damage, and to be required for p97 recruitment. DVC1's localization to DNA damage sites requires its UBZ domain and PCNA-interacting motif but not PCNA ubiquitination. DVC1 deficiency caused retention of error-prone translesion polymerase η at foci after UV-light damage and increased mutagenesis levels.

In a quantitative proteomics approach, Mailand, Choudhary and colleagues characterize ultraviolet-regulated ubiquitylation sites and identify a role for double mono-ubiquitylation of PCNA-associated factor PAF15 in bypassing replication-blocking lesions in DNA.

Bass et al. and Haahr et al. now identify ETAA1 as a critical replication stress response factor that interacts with DNA damage response proteins and activates ATR to maintain genomic stability.

At the initiation of DNA double-strand break repair, a number of ubiquitylation events occur; here, the RNF8 ubiquitin E3 ligase and the ubiquitin-conjugating E2 enzyme, UBC13, are shown to primarily modify H1-type linker histones, via a K63 linkage.

We have a limited understanding of how cells mark and identify newly replicated genomic loci that have a sister chromatid; here, unmethylated K20 in the tail of new histone H4 is shown to serve as a signature of post-replicative chromatin, which is specifically recognized by the homologous recombination complex TONSL–MMS22L.