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Homologous Recombination-Mediated DNA Repair and Implications for Clinical Treatment of Repair Defective Cancers

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DNA Repair

Part of the book series: Methods in Molecular Biology ((MIMB,volume 1999))

Abstract

Double-strand DNA breaks (DSBs) are generated by ionizing radiation and as intermediates during the processing of DNA, such as repair of interstrand cross-links and collapsed replication forks. These potentially deleterious DSBs are repaired primarily by the homologous recombination (HR) and nonhomologous end joining (NHEJ) DNA repair pathways. HR utilizes a homologous template to accurately restore damaged DNA, whereas NHEJ utilizes microhomology to join breaks in close proximity. The pathway available for DSB repair is dependent upon the cell cycle stage; for example, HR primarily functions during the S/G2 stages while NHEJ can repair DSBs at any cell cycle stage. Posttranslational modifications (PTMs) promote activity of specific pathways and subpathways through enzyme activation and precisely timed protein recruitment and degradation. This chapter provides an overview of PTMs occurring during DSB repair. In addition, clinical phenotypes associated with HR-defective cancers, such as mutational signatures used to predict response to poly(ADP-ribose) polymerase inhibitors, are discussed. Understanding these processes will provide insight into mechanisms of genome maintenance and likely identify targets and new avenues for therapeutic interventions.

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Notes

  1. 1.

    Boveri’s original manuscript was published in 1914, and the 2008 reference is an English translation by Henry Harris.

Abbreviations

DSBs:

Double-strand breaks

dsDNA:

Double-stranded DNA

HR:

Homologous recombination

ICLs:

Interstrand cross-links

NHEJ:

Nonhomologous end joining

PARP:

Poly(ADP)-ribose polymerase

PTMs:

Posttranslational modifications

SSBs:

Single-strand breaks

ssDNA:

Single-stranded DNA

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Acknowledgments

We would like to thank Michael Wyatt, Janay Clytus, and Jason Stewart for insightful comments and suggestions during the writing of this review. The work related to the topic of this chapter was supported by a grant from the National Institute of General Medical Sciences of the National Institutes of Health Award Number R15 GM110615 and the American Cancer Society (RSG-03-158-01-GMC). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Additional support was provided to NMR from a SPARC Graduate Research Grant from the Office of the Vice President for Research at the University of South Carolina and from an Associazione Italiana per la Ricerca sul Cancro “Molini Bongiovanni” Fellowship.

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Authors and Affiliations

  1. Fondazione Piemontese per la Ricerca sul Cancro ONLUS, Candiolo, Italy

    Nicole M. Reilly

  2. Department of Translational Hematology and Oncology Research, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA

    Brian D. Yard

  3. Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, Columbia, SC, USA

    Douglas L. Pittman

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  1. Nicole M. Reilly
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  2. Brian D. Yard
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Correspondence to Douglas L. Pittman .

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Editors and Affiliations

  1. Indiana University – Purdue University, Indianapolis, IN, USA

    Lata Balakrishnan

  2. Department of Biological Sciences, University of South Carolina, Columbia, SC, USA

    Jason A. Stewart

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Reilly, N.M., Yard, B.D., Pittman, D.L. (2019). Homologous Recombination-Mediated DNA Repair and Implications for Clinical Treatment of Repair Defective Cancers. In: Balakrishnan, L., Stewart, J. (eds) DNA Repair. Methods in Molecular Biology, vol 1999. Humana, New York, NY. https://doi.org/10.1007/978-1-4939-9500-4_1

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  • Online ISBN: 978-1-4939-9500-4

  • eBook Packages: Springer Protocols

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