Homologous recombination (HR) represents a major, evolutionarily conserved chromosome damage repair tool. By eliminating radiation-induced DNA double-strand breaks and other deleterious chromosome lesions, HR is critical for the maintenance of genome stability. In humans, defects in HR directly lead to the cancer phenotype. This renewal research project focuses on the roles that two tumor suppressors, BRCA2 and PALB2, and their partner proteins fulfill in the HR-mediated repair of damaged chromosomes. Considerable progress has been made during the last funding period, leading to important advances in understanding HR mechanism. Capitalizing on our success, a variety of in vitro and in vivo studies will be conducted to delineate the multi- faceted roles of the BRCA2-PALB2 complex and associated proteins in the HR reaction. Novel hypotheses regarding how the HR factors facilitate the presynaptic and synaptic stages of the HR reaction will be tested. We fully anticipate the results from this renewal project to continue providing insights regarding the functions of key HR factors, and to allow us to formulate detailed models of the BRCA2-PALB2 axis of chromosome damage repair in human cells. Given the importance of HR in tumor suppression and in the removal of DNA crosslinks induced by chemotherapeutic agents, our studies have direct relevance to cancer biology and to the development of molecules to evaluate the potential of HR pathway-targeted therapeutic strategies. Moreover, the research materials generated during the course of our studies represent an invaluable resource for the DNA repair and cancer biology research communities.

Public Health Relevance

Failure to repair damaged chromosomes compromises the integrity of the genome and can lead to cancer formation. The proposed studies will delineate the role of two well- known tumor suppressors and their partner proteins in the homologous recombinational repair of chromosomes that harbor radiation-induced double-strand breaks and other deleterious lesions. The results will make a major contribution toward delineating the mechanism of HR in human cells and have direct relevance to understanding the role of DNA repair in cancer avoidance.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES015252-08
Application #
8580935
Study Section
Special Emphasis Panel (ZRG1-OBT-A (02))
Program Officer
Reinlib, Leslie J
Project Start
2006-12-15
Project End
2016-10-31
Budget Start
2013-12-01
Budget End
2014-11-30
Support Year
8
Fiscal Year
2014
Total Cost
$368,007
Indirect Cost
$111,491
Name
Yale University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Kumar, S; Peng, X; Daley, J et al. (2017) Inhibition of DNA2 nuclease as a therapeutic strategy targeting replication stress in cancer cells. Oncogenesis 6:e319
Ma, Chu Jian; Gibb, Bryan; Kwon, YoungHo et al. (2017) Protein dynamics of human RPA and RAD51 on ssDNA during assembly and disassembly of the RAD51 filament. Nucleic Acids Res 45:749-761
Xu, Jingfei; Zhao, Lingyun; Xu, Yuanyuan et al. (2017) Cryo-EM structures of human RAD51 recombinase filaments during catalysis of DNA-strand exchange. Nat Struct Mol Biol 24:40-46
Trego, Kelly S; Groesser, Torsten; Davalos, Albert R et al. (2016) Non-catalytic Roles for XPG with BRCA1 and BRCA2 in Homologous Recombination and Genome Stability. Mol Cell 61:535-546
Liang, Fengshan; Longerich, Simonne; Miller, Adam S et al. (2016) Promotion of RAD51-Mediated Homologous DNA Pairing by the RAD51AP1-UAF1 Complex. Cell Rep 15:2118-2126
Borgogno, MarĂ­a V; Monti, Mariela R; Zhao, Weixing et al. (2016) Tolerance of DNA Mismatches in Dmc1 Recombinase-mediated DNA Strand Exchange. J Biol Chem 291:4928-38
Gaines, William A; Godin, Stephen K; Kabbinavar, Faiz F et al. (2015) Promotion of presynaptic filament assembly by the ensemble of S. cerevisiae Rad51 paralogues with Rad52. Nat Commun 6:7834
Zhao, Weixing; Sung, Patrick (2015) Significance of ligand interactions involving Hop2-Mnd1 and the RAD51 and DMC1 recombinases in homologous DNA repair and XX ovarian dysgenesis. Nucleic Acids Res 43:4055-66
Parplys, Ann C; Zhao, Weixing; Sharma, Neelam et al. (2015) NUCKS1 is a novel RAD51AP1 paralog important for homologous recombination and genome stability. Nucleic Acids Res 43:9817-34
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

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