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Modernizing the Nonhomologous End-Joining Repertoire: Alternative and Classical NHEJ Share the Stage

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Modernizing the Nonhomologous End-Joining Repertoire: Alternative and Classical NHEJ Share the Stage Modernizing the nonhomologous end-joining repertoire: alternative and classical NHEJ share the stage. Ludovic Deriano, David B Roth To cite this version: Ludovic Deriano, David B Roth. Modernizing the nonhomologous end-joining repertoire: alternative and classical NHEJ share the stage.. Annual Review of Genetics, Annual Reviews, 2013, 47 (1), pp.433-55. 10.1146/annurev-genet-110711-155540. pasteur-01471700 HAL Id: pasteur-01471700 https://hal-pasteur.archives-ouvertes.fr/pasteur-01471700 Submitted on 27 Mar 2017 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. GE47CH19-Deriano ARI 23 October 2013 16:5 Modernizing the Nonhomologous End-Joining Repertoire: Alternative and Classical NHEJ Share the Stage Ludovic Deriano1 and David B. Roth2 1Departments of Immunology and Genomes & Genetics, Institut Pasteur, CNRS-URA 1961, 75015 Paris, France; email: [email protected] 2Department of Pathology and Laboratory Medicine and Abramson Cancer Family Research Institute, Raymond and Ruth Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104; email: [email protected] Annu. Rev. Genet. 2013. 47:433–55 Keywords First published online as a Review in Advance on classical nonhomologous end joining, alternative nonhomologous end September 11, 2013 joining, DNA damage response, DNA double-strand breaks, V(D)J The Annual Review of Genetics is online at recombination, genomic instability genet.annualreviews.org This article’s doi: Abstract 10.1146/annurev-genet-110711-155540 DNA double-strand breaks (DSBs) are common lesions that continually Copyright c 2013 by Annual Reviews. threaten genomic integrity. Failure to repair a DSB has deleterious con- All rights reserved sequences, including cell death. Misrepair is also fraught with danger, especially inappropriate end-joining events, which commonly underlie Annu. Rev. Genet. 2013.47:433-455. Downloaded from www.annualreviews.org oncogenic transformation and can scramble the genome. Canonically, cells employ two basic mechanisms to repair DSBs: homologous re- combination (HR) and the classical nonhomologous end-joining path- Access provided by Institut Pasteur - Paris Bibliotheque Centrale on 10/18/16. For personal use only. way (cNHEJ). More recent experiments identified a highly error-prone NHEJ pathway, termed alternative NHEJ (aNHEJ), which operates in both cNHEJ-proficient and cNHEJ-deficient cells. aNHEJ is now recognized to catalyze many genome rearrangements, some leading to oncogenic transformation. Here, we review the mechanisms of cNHEJ and aNHEJ, their interconnections with the DNA damage response (DDR), and the mechanisms used to determine which of the three DSB repair pathways is used to heal a particular DSB. We briefly review recent clinical applications involving NHEJ and NHEJ inhibitors. 433 GE47CH19-Deriano ARI 23 October 2013 16:5 INTRODUCTION which can initiate neoplastic transformation by a variety of mechanisms. One is through DNA double-strand breaks (DSBs), although formation of chimeric oncogenes, the classic DSB: double-strand common, are extremely dangerous (Figure 1). example being the translocation between break Unlike most other DNA lesions, DSBs directly chromosomes 9 and 22 in chronic myeloid threaten genomic integrity by disrupting the leukemia (CML), forming the Philadelphia physical continuity of the chromosome. With- chromosome (86) and creating the novel bcr-abl out repair, all genetic material telomeric to the oncogene. Indeed, studies done before cancer break is lost at the next cell division. A second genome sequencing became commonplace particular threat posed by DSBs arises from identified more than 300 gene fusions in repair mechanisms themselves, which, if not human neoplasms, and these are believed to executed properly, possess formidable power to account for approximately 20% of human wreak genomic havoc. Misrepair of DSBs can, cancer (83). This number is likely to grow as of course, cause localized sequence alterations more cancer genomes are studied in depth. and loss of genomic material. Arguably more Complex genomic rearrangements are dangerous, however, is inappropriate joining also initiated by joining two centromere- of the wrong pair of DNA ends. Inappropriate bearing chromosome fragments together. joining can generate interstitial deletions, This initiates a cascade of persistent cycles inversions, and chromosome translocations, Nonprogrammed Programmed e.g., Ionizing radiation e.g., V(D)J recombination Genotoxic drugs Class switch recombination Replication errors Meiosis DSB Sensing [Ku, MRE11 complex, Parp1] Signal transduction [ATM] Annu. Rev. Genet. 2013.47:433-455. Downloaded from www.annualreviews.org Cell-cycle arrest DNA repair Responses Apoptosis [HR, cNHEJ, aNHEJ] Senescence Access provided by Institut Pasteur - Paris Bibliotheque Centrale on 10/18/16. For personal use only. Cancer Cell death DEREGULATION GENOMIC INSTABILITY Figure 1 Schematic of cell responses, and their potential pitfalls, to double-strand breaks (DSBs). Abbreviations: aNHEJ, alternative nonhomologous end joining; ATM, ataxia telangiectasia mutated; cNHEJ, classical nonhomologous end joining; HR, homologous recombination. 434 Deriano · Roth GE47CH19-Deriano ARI 23 October 2013 16:5 of chromosome fragmentation and aberrant CHALLENGES FACED BY rejoining (81), leading to complex deletions/ DOUBLE-STRAND-BREAK translocations/amplifications termed compli- REPAIR SYSTEMS cons (149). Such complex rearrangements often Given the foregoing discussion, we can postu- accompany gross chromosome rearrangements late some basic requirements for an effective (149). Even more complex genome scram- DSB repair system: (a) high sensitivity, allow- bling arises from a recently described process ing detection of a single DSB, and the ability termed chromothripsis, defined as chromo- to do so rapidly enough to allow proper repair some shattering and reassembling, which before a catastrophic event occurs; (b) a great involves multiple simultaneous DSBs and degree of specificity—the system must detect misrepair. Again, cancer-causing lesions can DSBs but not nicks, mismatches, abasic sites, emerge from such catastrophic genomic events or interstrand crosslinks, which require distinct (47). repair systems; (c) the ability to repair breaks with a high degree of fidelity (without too much COMMON LESIONS WITH collateral genomic damage); (d ) the capacity to MANY SOURCES repair a variety of different kinds of DNA ends, Given the dire consequences that can attend the including those that are not directly ligatable failure to properly repair broken DNA ends, it (produced, for example, by certain forms of ir- is (at least from the perspective of cancer bi- radiation and by reactive oxygen species); and ologists) unnerving that DSBs occur quite fre- (e) the ability to coordinate DSB repair with the quently. Endogenous sources of DSBs include physiological state of the cell (e.g., the timing fragile sites, errors in DNA metabolism (e.g., of repair with respect to cell-cycle status). replication across single-strand nicks and repli- These requirements are further complicated cation fork collapse), endogenous nucleases, by genome size, structure, and organization. programmed genome rearrangements, physical Mammalian genomes are large, requiring DSB forces, and reactive oxygen species. Numerous repair systems to possess extraordinary sensi- DSBs of exogenous origin, both natural (e.g., tivity (one part per billion) and to be able to cosmic rays, terrestrial background radiation, consistently detect individual molecular signals certain viruses) and man-made (e.g., weapons (such sensitivity parallels another sensory sys- of mass destruction and diagnostic and thera- tem, the rod photoreceptor, which can respond peutic maneuvers), threaten the genome. The to single photons). A second challenge is posed latter category includes diagnostic radiographs, by genomic heterogeneity. The accessibility radiation therapy, genotoxic drugs used for can- of a particular DNA sequence varies widely cer therapy, and gene-therapy strategies, which with genomic context and/or physical location. Surveillance mechanisms must reliably detect Annu. Rev. Genet. 2013.47:433-455. Downloaded from www.annualreviews.org can employ nucleases to induce DSBs in a de- sired target sequence (27, 45) but which can also and repair all DSBs, even those in less accessible cleave unintended (off-target) sequences (92). locations, such as highly condensed chromatin and specialized subnuclear compartments (al- Access provided by Institut Pasteur - Paris Bibliotheque Centrale on 10/18/16. For personal use only. An interesting estimate of the number of DSBs attending some of these exposures follows: a though not necessarily with the same rapid- 10-hour flight from Philadelphia to Paris re- ity). A third difficulty is raised by the fact that sults in 0.05 DSB per cell; a body CT scan, 0.3 mammalian genomes contain a high proportion DSB per cell; the Chernobyl accident, 12 DSBs of dispersed, highly repetitive DNA
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