Trends in Cell Biology
OpinionCoupling DNA Damage and Repair: an Essential Safeguard during Programmed DNA Double-Strand Breaks?
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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