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Mechanisms and regulation of DNA end resection in the maintenance of genome stability

Nature Reviews Molecular Cell Biology volume 26, pages 586–599 (2025)Cite this article

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Abstract

DNA end resection is a crucial early step in most DNA double-strand break (DSB) repair pathways. Resection involves the nucleolytic degradation of 5′ ends at DSB sites to generate 3′ single-stranded DNA overhangs. The first, short-range resection step is catalysed by the nuclease MRE11, acting as part of the MRE11–RAD50–NBS1 complex. Subsequent long-range resection is catalysed by the nucleases EXO1 and/or DNA2. Resected DNA is necessary for homology search and the priming of DNA synthesis in homologous recombination. DNA overhangs may also mediate DNA annealing in the microhomology-mediated end-joining and single-strand annealing pathways, and activate the DNA damage response. By contrast, DNA end resection inhibits DSB repair by non-homologous end-joining. In this Review, we discuss the importance of DNA end resection in various DSB repair pathways, the molecular mechanisms of end resection and its regulation, focusing on phosphorylation and other post-translational modifications that control resection throughout the cell cycle and in response to DNA damage.

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Fig. 1: DNA end processing in various DSB repair pathways.
Fig. 2: Mechanism of short-range and long-range resection.
Fig. 3: Regulation of DNA end resection by CtIP phosphorylation.

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Acknowledgements

This work has received fundings from the French ARC foundation for cancer research (label program, grant ARGPGA2023110007360_7961), La Ligue (grant RS24/75-14) and the French National Research Agency (ANR) (grant ANR-23-CE12-0032) for the Ceccaldi laboratory. The Swiss National Science Foundation (SNSF) (grants 310030_207588 and 310030_205199) and the European Research Council (ERC) (grant 101018257) support the research in the Cejka laboratory. We thank members of the Cejka laboratory for critical comments on the manuscript.

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Authors and Affiliations

  1. INSERM U830, PSL Research University, Institut Curie, Paris, France

    Raphael Ceccaldi

  2. Institute for Research in Biomedicine, Università della Svizzera italiana, Bellinzona, Switzerland

    Petr Cejka

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  1. Raphael Ceccaldi
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  2. Petr Cejka
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The authors contributed equally to all aspects of the article.

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Correspondence to Raphael Ceccaldi or Petr Cejka.

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Nature Reviews Molecular Cell Biology thanks Patrick Sung, David Yu, who co-reviewed with Sandip Kumar Rath, and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Glossary

BRCA1–C complex

Contains the BRCA1–BARD1 heterodimer, CtIP and MRN. Binds to sites of DNA damage and promotes DNA end resection.

BRCA1–PALB2–BRCA2 complex

Protein complex crucial for homologous recombination, in which PALB2 bridges BRCA1 and BRCA2, thereby enabling RAD51 loading at resected ends.

Break-induced replication (BIR)

A mutagenic subpathway of homologous recombination, in which one broken DNA end invades a homologous template and initiates DNA synthesis that often proceeds to the end of chromosomal DNA, without engaging a second DNA end.

Degradation of nascent DNA

An enzymatic process leading to the removal of newly synthesized DNA at reversed forks or post-replication gaps.

Hairpin-capped ends

A DNA break in which one the strand folds back on itself, forming a hairpin-like loop structure.

Homologous recombination (HR)

A high-fidelity DNA break repair pathway that uses a homologous sequence from the sister chromatid as a repair template, and which can give rise to crossovers.

Long-range end resection

Extended trimming of DSBs by the nucleases EXO1 or DNA2, producing long ssDNA overhangs.

Microhomology-mediated end-joining (MMEJ)

An error-prone DNA repair pathway that relies on short homologous DNA sequences near break sites, often resulting in small insertions and/or deletions.

Non-homologous end-joining (NHEJ)

A fast DNA repair pathway that ligates broken ends without requiring sequence homology, often causing small insertions or deletions at the break site.

Replication-fork reversal

Conversion of standard three-stranded replication fork into a four-stranded junction, resulting from backtracking of the replication fork.

Short-range end resection

Initial trimming of DSBs by the MRN complex and its cofactor CtIP, producing ssDNA overhangs.

Single-ended DSB

A DSB in which only one DNA end is present, typically resulting from the collapse of a DNA replication fork.

Single-strand annealing (SSA)

An error-prone DNA repair pathway that uses long homologous sequences flanking a DSB, often leading to large deletions.

ssDNA gaps

Stretches of ssDNA on newly replicated DNA.

Synthesis-dependent strand annealing (SDSA)

A high-fidelity subpathway of HR, in which the invading strand is extended by DNA synthesis and then re-anneals with the complementary sequence to complete repair without crossover formation.

T-loop

A protective DNA structure formed at telomeres.

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Ceccaldi, R., Cejka, P. Mechanisms and regulation of DNA end resection in the maintenance of genome stability. Nat Rev Mol Cell Biol 26, 586–599 (2025). https://doi.org/10.1038/s41580-025-00841-4

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