The major pathways of DNA double-strand break (DSB) repair are crucial for maintaining genomic stability. However, if deployed in an inappropriate cellular context, these same repair functions can mediate chromosome rearrangements that underlie various human diseases, ranging from developmental disorders to cancer. The two major mechanisms of DSB repair in mammalian cells are non-homologous end joining (NHEJ) and homologous recombination. In this Review, we consider DSB repair-pathway choice in somatic mammalian cells as a series of ‘decision trees’, and explore how defective pathway choice can lead to genomic instability. Stalled, collapsed or broken DNA replication forks present a distinctive challenge to the DSB repair system. Emerging evidence suggests that the ‘rules’ governing repair-pathway choice at stalled replication forks differ from those at replication-independent DSBs.
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The authors thank Johannes Walter, Joe Loparo, Andre Nussenzweig, Stephen Jackson, Edison Liu, David Cortez, Agata Smogorzewska and the Scully laboratory members for helpful discussions and for sharing unpublished research findings. This work was supported by awards R01CA095175, R01CA217991, OC160440, BC160172P1 and R21ES027776 (to R.S.) and P50CA168504 (to N.A.W.).
Nature Reviews Molecular Cell Biology thanks P. Čejka and the other anonymous reviewer(s) for their contribution to the peer review of this work.
The authors declare no competing interests.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
- One-ended breaks
Solitary DNA ends that lack an immediate second DNA end for rejoining or annealing.
- Stalled replication forks
Replication forks that have been arrested at DNA damage sites or because of other causes.
A DNA and protein complex in which two DNA molecules are brought into close proximity with the assistance of their associated proteins.
- PARP inhibitors
Inhibitors of poly(ADP-ribose) polymerase (PARP) (especially PARP1) induce synthetic lethality in homologous recombination mutant cells through an unresolved mechanism that involves trapping of PARP1 on DNA.
- χ sequences
Short sequences in bacterial genomes that serve as ‘hotspots’ for recombination; no equivalent has been identified in vertebrates.
- Gene conversion
The transfer of genetic material from a donor sequence to a homologous acceptor during homologous recombination.
- Translesion DNA polymerases
Specialized DNA polymerases that can traverse a damaged and unreadable DNA template.
- Holliday junction
A four-way branched DNA structure that can mediate reciprocal exchanges between two homologous DNA molecules.
A repair pathway that does not result in crossing over.
- Crossing over
The exchange of genetic material between two homologous chromosomes.
- Broken replication forks
Stalled replication forks that have lost their branched DNA structure due to interruption of both DNA strands of at least one sister chromatid.
- Collapsed replication forks
Stalled replication forks that have lost the capacity to perform DNA synthesis due to disassembly of the replisome.
- Replication restart
Resumption of DNA synthesis at a stalled fork; may be mediated by conventional semiconservative DNA synthesis or by error-prone mechanisms.
- Migrating bubble
DNA synthesis mechanism of long-tract gene conversion and break-induced replication.
- Daughter strand gaps
(DSGs). Post-replicative DNA single-strand gaps caused by interruption of the synthesis of the nascent daughter strand.
Localized chromosome shattering and repair that occurs as a one-off catastrophe, generating an alternating copy number profile at the affected locus.
A closed chain of linked translocations, with little or no copy number alteration, observed in some cancers.
The first stage of mitosis, during which chromosomes begin to condense.
Topological entanglements of two double-stranded DNA molecules, in which one strand of each duplex passes between the two strands of the other duplex.
- Fork reversal
A stalled and collapsed replication fork in which reannealing of the parental strands has moved the branch-point of the fork backwards, extruding the annealed nascent strands to form a ‘chicken foot’ four-way DNA junction.
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Scully, R., Panday, A., Elango, R. et al. DNA double-strand break repair-pathway choice in somatic mammalian cells. Nat Rev Mol Cell Biol 20, 698–714 (2019). https://doi.org/10.1038/s41580-019-0152-0
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