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Regulation of DNA repair throughout the cell cycle

Key Points

  • The repair of DNA lesions that occur endogenously or in response to diverse genotoxic stresses is indispensable for maintaining genome integrity.

  • The types of DNA lesion and the checkpoint pathways that are activated in response to DNA damage influence the DNA-repair pathways according to the cell-cycle phase.

  • Failure to coordinate DNA repair with cell-cycle progression can cause genome instability, cell death and cancer.

  • Phosphorylation events that are mediated by cyclin-dependent kinases and checkpoints regulate DNA repair according to the cell-cycle stage.

  • Certain DNA-repair pathways are attenuated in non-dividing cells that probably possess dedicated mechanisms to repair endogenous lesions.

  • SUMO and ubiquitin modifications are crucial in the regulation of the stability and activity of key components of DNA repair and checkpoint machineries, thereby regulating important cell-cycle events.

Abstract

The repair of DNA lesions that occur endogenously or in response to diverse genotoxic stresses is indispensable for genome integrity. DNA lesions activate checkpoint pathways that regulate specific DNA-repair mechanisms in the different phases of the cell cycle. Checkpoint-arrested cells resume cell-cycle progression once damage has been repaired, whereas cells with unrepairable DNA lesions undergo permanent cell-cycle arrest or apoptosis. Recent studies have provided insights into the mechanisms that contribute to DNA repair in specific cell-cycle phases and have highlighted the mechanisms that ensure cell-cycle progression or arrest in normal and cancerous cells.

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Figure 1: Cell-cycle-specific DNA structures and lesions and the checkpoint kinases that respond to them.
Figure 2: cyclin-dependent-kinase- and checkpoint-mediated regulatory processes influence DNA-repair pathways.
Figure 3: Repair of double-strand breaks by non-homologous end joining and homologous recombination.
Figure 4: Sumoylation and ubiquitylation events that are implicated in modulation of DNA repair.

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Acknowledgements

The authors apologize for the many interesting articles that could not be cited here owing to space limitations. The work in the authors' laboratories is supported by grants form the Associazione Italiana per la Ricerca sul Cancro, the European Community, Telethon-Italy, the Italian Ministry of Education and the Association for International Cancer Research to M.F. and D.B. D.B. is supported by the Buzzati-Traverso foundation.

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Glossary

Replication fork

The branch-point structure that forms during DNA replication between the two template DNA strands where nascent DNA synthesis is ongoing.

Cyclin-dependent kinases

A group of serine/threonine protein kinases that are activated at specific points during the cell cycle, together with their regulatory cyclin subunits. They regulate cell-cycle transitions by inducing degradation of cell-cycle inhibitory proteins.

Apoptosis

A form of programmed cell death that is well defined in multicellular organisms.

Stalled fork

A replication fork at which progress is blocked. Progress may be blocked by the presence of bulky lesions, aberrant DNA structures, protein–DNA complexes or depletion of dNTP pools.

Collapsed forks

Disjunction of the two partially replicated sister duplexes at the replication fork that is usually associated with the dissociation of the replisome from the replication fork.

Replisome

Protein machinery that is required to replicate DNA.

Translesion-synthesis polymerases

Low-fidelity and non-processive polymerases that can be used to bypass DNA lesions at the replication fork, often in an error-prone way.

Template switch

(TS). A process that repairs gaps in newly replicated DNA. TS can occur, for example, when a replicative polymerase encounters a lesion on the parental strand. TS uses the information on the newly synthesized sister chromatid as a template to fill in the gaps.

Topoisomerases

Enzymes that remove torsional stress from double-stranded DNA by breaking and rejoining one or two of the DNA strands.

Supercoils

Contortions in DNA that are important for DNA packaging and DNA–RNA synthesis. Topoisomerases sense supercoiling and can either generate or dissipate it by changing DNA topology.

Precatenanes

Cruciform junctions that are formed by the intertwining of the sister duplexes in the replicated portion of a replicone.

Damage tolerance

A post-replicative repair pathway in which the lesions are not repaired, but bypassed (tolerated) during replication. Bypass can be achieved by either using specialized polymerases, or by using the newly synthesized sister chromatid strand as a template.

Epistasis

A group of genes that function in the same biological pathway, usually defined by genetic analysis of double mutants.

Poly(ADP-ribose) polymerase

A polymerase that attaches ADP–ribose moieties to target proteins by means of covalent bonds, which is one of the earliest cellular responses to strand breaks.

Differentiated cells

Cells that are specialized for a particular function (such as neurons and muscle cells) and that cannot proliferate.

Senescent cells

Mitotic cells that cannot divide, but remain metabolically active. Senescence is often caused by stimuli that can cause cancer.

Double Holliday junction

A central intermediate to homologous recombination.

Ischaemia

A restriction in blood supply, generally due to factors in the blood vessels, that causes tissue damage or dysfunction.

RecQ helicase

A family of helicase enzymes that is important for genome maintenance. They function through unwinding paired DNA and translocate in the 3′→5′ direction.

Fanconi anaemia

A rare genetically inherited disorder that is characterized by congenital abnormalities and increased incidence of cancer.

Srs2

A budding yeast DNA helicase that functions to prevent recombination by disrupting Rad51 filaments.

BRCA1

The product of the first breast cancer susceptibility gene; it is involved in DNA repair, cell-cycle regulation and protein ubiquitylation.

BRCA2

A tumour suppressor and an integral component of the homologous-recombination machinery.

BRCT repeats

A protein motif with homology to the C-terminal region of BRCA1 that constitutes a phosphopeptide-recognition domain.

Hemicatenanes

Cruciform junctions of two double-stranded DNA molecules in which one of the strands of one duplex passes between the two strands of the other duplex (and vice versa).

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Branzei, D., Foiani, M. Regulation of DNA repair throughout the cell cycle. Nat Rev Mol Cell Biol 9, 297–308 (2008). https://doi.org/10.1038/nrm2351

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