Trends in Cell Biology
Volume 30, Issue 2, February 2020, Pages 87-96
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Opinion
Coupling DNA Damage and Repair: an Essential Safeguard during Programmed DNA Double-Strand Breaks?

https://doi.org/10.1016/j.tcb.2019.11.005Get rights and content

Highlights

  • Several biological processes [meiosis, V(D)J recombination, PGR in ciliates, and signal-induced transcription] proceed via introduction of prDSBs.

  • DSBs being the most toxic DNA lesions, as potentially oncogenic, prDSBs are likely associated with efficient, multilayered DNA repair mechanisms. Coupling DNA damage and repair is one critical layer.

  • Ku80 is a critical factor to link DNA damage and repair during PGR in ciliates.

  • The C terminus of RAG2 may be responsible for the DNA damage–repair coupling during V(D)J recombination as a safeguard against genome instability.

  • During meiotic recombination, a specific pathway ensures that meiotic DSBs are formed within the correct spatial chromosomal context.

  • The MRE11 complex is required for the formation of prDSBs by Spo11 during meiotic recombination.

  • DNA damage–repair coupling may represent an essential step in the domestication process of PiggyMac, RAG1/2 and other transposases.

DNA double-strand breaks (DSBs) are the most toxic DNA lesions given their oncogenic potential. Nevertheless, programmed DSBs (prDSBs) contribute to several biological processes. Formation of prDSBs is the ‘price to pay’ to achieve these essential biological functions. Generated by domesticated PiggyBac transposases, prDSBs have been integrated in the life cycle of ciliates. Created by Spo11 during meiotic recombination, they constitute a driving force of evolution and ensure balanced chromosome content for successful reproduction. Produced by the RAG1/2 recombinase, they are required for the development of the adaptive immune system in many species. The coevolution of processes that couple introduction of prDSBs to their accurate repair may constitute an effective safeguard against genomic instability.

Introduction

Living organisms are constantly exposed to genotoxic assaults, which can be of endogenous origin, such as cellular respiration or exogenous sources such as radiation or chemical exposure. Several highly conserved DNA repair mechanisms have been selected during evolution to cope with these various damages and maintain genomic integrity. Among DNA lesions, double-strand breaks (DSBs; see Glossary) are considered the most toxic and at least two DNA repair pathways [homologous recombination (HR) and nonhomologous end joining (NHEJ)] have evolved to cope with DSBs. In addition to repairing pathological DSBs, these DNA repair pathways are also important for the repair of physiological DSBs or prDSBs created during programmed genome rearrangements (PGRs) in ciliates, meiotic recombination for sexual reproduction, and V(D)J recombination. Defects in these processes result in death of progeny (PGR), sterility or aneuploidy (meiotic recombination), and severe immune deficiency (V(D)J recombination). Therefore, the introduction of prDSBs is ‘the price to pay’ for some physiological processes. One can argue that efficient ways to control prDSBs have coevolved to avoid the deleterious consequences of their misrepair. Here, we discuss the view that the timely and physical coupling of DNA damage and repair may represent an efficient safeguard during prDSBs.

Section snippets

Coupling DNA Damage and NHEJ-Mediated Repair of prDSBs?

NHEJ is one of the two main DSB repair mechanisms. It operates in all phases of the cell cycle, in contrast to HR, which is excluded from G0/G1. Its catalytic process can be schematically divided into three steps. (i) The heterodimer Ku70/80 identifies and is recruited to the break, prior to the recruitment of the DNA-dependent protein kinase catalytic subunit DNA-PKcs, forming the DNAPK holoenzyme. (ii) If needed, DNA ends are processed (cleaned) by DNA polymerases, nucleases, and kinases. The

Meiotic recombination: HR Is Also Concerned

As opposed to NHEJ, HR uses DNA sequence homology on an intact DNA template to repair the broken DNA molecule after a DSB. The repair template can be located on the sister chromatid, on a homologous chromosome, or elsewhere in the genome. The first step of HR is the resection of the 5′ ends of the DSBs, first by the MRE11 complex, then by EXO1 and BLM/DNA2, which generates protruding 3′ ends that invade the DNA repair template, through the action of a RecA-related recombinase, such as Rad51 [57

Concluding Remarks

Besides meiosis, PGR, and V(D)J recombination, prDSBs have been identified during signal-induced transcription in several experimental settings [81]. These activity-induced prDSBs occur primarily in early response genes and are introduced by the topoisomerase IIβ. This is in particular the case in the response of MCF-7 cells to estradiol [82] or activation through glucocorticoid receptors [83]. prDSBs also occur in vivo and in vitro upon neuronal activity [84,85]. In the case of the

Acknowledgments

We thank Mathilde Grelon (INRA, Versailles) for personal communication. Work in our respective laboratories is supported by institutional grants from INSERM, CNRS, ANR (‘Investissements d’avenir’ program ANR-10-IAHU-01; ANR-13-PRTS-0004; ANR-18-CE12-0018; ANR-14-CE10-0005-01; and ANR-18-CE12-0005-02), INCa (PLBIO16-280), and grants from Ligue Nationale Contre le Cancer (Equipe Labellisée), Fondation pour la Recherche Médicale (Equipe FRM EQU201903007785), and AT-Europe Foundation.

Glossary

Double-strand breaks
DNA DSBs can be accidental as a result of environmental insult or programmed (prDSBs) as part of essential physiological processes (meiosis, V(D)J recombination, or PGR in ciliates).
Homologous recombination
repair pathway that is one of the two main mechanisms, with NHEJ, to repair DSBs. It operates in the S and G2 phases of the cell cycle when a sister chromatid is available as template.
Meiosis
process of chromosome segregation during the formation of gametes. prDSBs are

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