Ionizing radiation, mutagenic chemicals, and replication of a damaged DNA template create DNA double-stranded breaks. If not handled properly, these breaks can lead to gross chromosome rearrangements and genome destabilization. Homologous recombination represents a major, conserved mechanism for the elimination of DNA double-strand breaks. Importantly, there is compelling evidence showing that even a minor deficiency in HR leads to disorders with a strong cancer predisposition in humans. Understanding the mechanisms of DSB repair by HR is highly relevant to radiation biology and also cancer biology. Over the past several decades, there has been great progress in identifying key enzymes and dissecting the mechanisms of HR, with major contributions coming from studies in the budding yeast S. cerevisiae. In this renewal project, we will tackle several outstanding questions germane for delineating the multi-faceted roles of the conserved DNA helicases Pif1 and Mph1 in the DNA synthesis step of recombination and recombination pathway choice, respectively. Moreover, we will determine how the Smc5-Smc6 complex influences the activity of the Mph1 helicase in DNA replication fork repair. The results from our continuing efforts will advance our understanding of the formation and resolution of DNA intermediates during the homologous repair of damaged chromosomes.

Public Health Relevance

Our studies focus on the mechanism by which eukaryotic cells eliminate highly mutagenic lesions, such as DNA double-stranded breaks that are induced by ionizing radiation and chemicals, from chromosomes. Importantly, defective chromosome damage repair is the underlying cause of several cancer-prone diseases and can pre-dispose affected individuals to a variety of cancers, including breast, ovarian, and pancreatic cancers. For these reasons, the studies outlined in the renewal application have direct relevance to public health.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM057814-14
Application #
8706889
Study Section
Radiation Therapeutics and Biology Study Section (RTB)
Program Officer
Janes, Daniel E
Project Start
1999-05-01
Project End
2017-03-31
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
14
Fiscal Year
2014
Total Cost
$297,827
Indirect Cost
$118,952
Name
Yale University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Xue, Xiaoyu; Papusha, Alma; Choi, Koyi et al. (2016) Differential regulation of the anti-crossover and replication fork regression activities of Mph1 by Mte1. Genes Dev 30:687-99
Black, Paul J; Miller, Adam S; Hayes, Jeffrey J (2016) Radioresistance of GGG sequences to prompt strand break formation from direct-type radiation damage. Radiat Environ Biophys 55:411-422
Niu, Hengyao; Potenski, Catherine J; Epshtein, Anastasiya et al. (2016) Roles of DNA helicases and Exo1 in the avoidance of mutations induced by Top1-mediated cleavage at ribonucleotides in DNA. Cell Cycle 15:331-6
Bonner, Jaclyn N; Choi, Koyi; Xue, Xiaoyu et al. (2016) Smc5/6 Mediated Sumoylation of the Sgs1-Top3-Rmi1 Complex Promotes Removal of Recombination Intermediates. Cell Rep 16:368-78
Krasner, Danielle S; Daley, James M; Sung, Patrick et al. (2015) Interplay between Ku and Replication Protein A in the Restriction of Exo1-mediated DNA Break End Resection. J Biol Chem 290:18806-16
Xue, Xiaoyu; Choi, Koyi; Bonner, Jaclyn N et al. (2015) Selective modulation of the functions of a conserved DNA motor by a histone fold complex. Genes Dev 29:1000-5
Xue, Xiaoyu; Sung, Patrick; Zhao, Xiaolan (2015) Functions and regulation of the multitasking FANCM family of DNA motor proteins. Genes Dev 29:1777-88
Daley, James M; Niu, Hengyao; Miller, Adam S et al. (2015) Biochemical mechanism of DSB end resection and its regulation. DNA Repair (Amst) 32:66-74
Daley, James M; Gaines, William A; Kwon, YoungHo et al. (2014) Regulation of DNA pairing in homologous recombination. Cold Spring Harb Perspect Biol 6:a017954
Xue, Xiaoyu; Choi, Koyi; Bonner, Jaclyn et al. (2014) Restriction of replication fork regression activities by a conserved SMC complex. Mol Cell 56:436-45

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