Roles of homologous recombination in response to ionizing radiation-induced DNA damage

Abstract

Purpose

Ionizing radiation induces a vast array of DNA lesions including base damage, and single- and double-strand breaks (SSB, DSB). DSBs are among the most cytotoxic lesions, and mis-repair causes small- and large-scale genome alterations that can contribute to carcinogenesis. Indeed, ionizing radiation is a ‘complete’ carcinogen. DSBs arise immediately after irradiation, termed ‘frank DSBs,’ as well as several hours later in a replication-dependent manner, termed ‘secondary’ or ‘replication-dependent DSBs. DSBs resulting from replication fork collapse are single-ended and thus pose a distinct problem from two-ended, frank DSBs. DSBs are repaired by error-prone nonhomologous end-joining (NHEJ), or generally error-free homologous recombination (HR), each with sub-pathways. Clarifying how these pathways operate in normal and tumor cells is critical to increasing tumor control and minimizing side effects during radiotherapy.

Conclusions

The choice between NHEJ and HR is regulated during the cell cycle and by other factors. DSB repair pathways are major contributors to cell survival after ionizing radiation, including tumor-resistance to radiotherapy. Several nucleases are important for HR-mediated repair of replication-dependent DSBs and thus replication fork restart. These include three structure-specific nucleases, the 3’ MUS81 nuclease, and two 5’ nucleases, EEPD1 and Metnase, as well as three end-resection nucleases, MRE11, EXO1, and DNA2. The three structure-specific nucleases evolved at very different times, suggesting incremental acceleration of replication fork restart to limit toxic HR intermediates and genome instability as genomes increased in size during evolution, including the gain of large numbers of HR-prone repetitive elements. Ionizing radiation also induces delayed effects, observed days to weeks after exposure, including delayed cell death and delayed HR. In this review we highlight the roles of HR in cellular responses to ionizing radiation, and discuss the importance of HR as an exploitable target for cancer radiotherapy.

Keywords:

• DNA repair
• DNA double-strand breaks
• homologous recombination
• ionizing radiation
• replication stress
• cancer radiotherapy

Acknowledgements

The authors thank S.M. LaRue, S.M. Bailey, Keara Boss, and members of our laboratories and academic departments for helpful discussions. Research in the Nickoloff lab was supported by NIH grant R01 GM084020, American Lung Association grant LCD-686552, the CSU Office of the Vice President for Research, and the Japan National Institute of Radiological Sciences Open Laboratory program. Research in the Hromas lab is supported by National Institutes of Health grant R01 CA139429.

Disclosure statement

The authors report no conflict of interest, including research supported by NIH grants R01 GM084020 and R01 CA139429.

Additional information

Notes on contributors

Jac A. Nickoloff

Jac A. Nickoloff, PhD, is a Professor in the Department of Environmental and Radiological Health Sciences, Colorado State University. His research focuses on DNA damage and repair, replication stress, and cancer cell biology.

Neelam Sharma

Neelam Sharma, PhD, is a Research Scientist in the Department of Environmental and Radiological Health Sciences, Colorado State University. Her research interests span biochemistry and molecular genetics of DNA repair with a focus on DNA double-strand break repair.

Christopher P. Allen

Christopher P. Allen, PhD, is a member of the Department of Microbiology, Immunology and Pathology and director of the Flow Cytometry and Cell Sorting Facility, Colorado State University. His research interests include DNA repair, radiobiology, and cancer cell signaling.

Lynn Taylor

Lynn Taylor, BS, is a member of Department of Environmental and Radiological Health Sciences, Colorado State University. Her research interests include space radiobiology and cancer biology.

Sage J. Allen

Sage J. Allen is a Biochemistry Major and Undergraduate Research Assistant in the Nickoloff lab.

Aruna S. Jaiswal

Aruna S. Jaiswal, PhD, is an Assistant Professor in the Department of Medicine and Division of Hematology and Oncology in the Long School of Medicine, University of Texas, San Antonio. His research focuses on inhibiting DNA repair pathways to enhance cancer cell death and improve cancer treatment.

Robert Hromas

Robert Hromas, MD, FACP, is Dean and Professor in the Department of Medicine and Division of Hematology and Oncology in the Long School of Medicine, University of Texas, San Antonio. He has long-standing research interests in genes involved in cancer cell growth and DNA repair, mechanisms of leukemia translocations, hematologic malignancies, and BRCA-defective cancers.