A functional machinery to repair DNA breaks is required for maintaining genome integrity and preventing tumourigenesis. In order to gain mechanistic insights into the complex DNA break repair network in mammalian cells, it is critical to identify novel factors that are required for each steps of the repair event. Equally, we need to define the roles of the known DNA break repair proteins, such as the RAD51 paralogs, as mutations in these proteins have been associated with increased cancer risks and decreased survival of cancer patients after cytotoxic therapies. Previously, we identified two of the RAD51 paralogs, RAD51C and XRCC3, as the essential components of Holliday junction resolvasome, a complex required for separate linked chromosomes during DNA break repair. This finding not only indicates a novel role of RAD51C and XRCC3 at the late stage of recombination but also in processing stalled replication forks. In addition, our studies also suggest functional interactions of the RAD51C complexes with ERCC1 and the RECQ helicases, both of which were important for processing recombination intermediates and stalled replication forks. Our goal is to define these unique functions of RAD51C complexes in recombinational repair that may explain their importance in genome maintenance and development.
The Specific Aims are: (1) Identification and characterization of novel RAD51C-interacting proteins in recombinational repair. (2) Analysis of the functional relationship between RAD51C complexes and ERCC1. (3) Biochemical analysis of the functional relationship between RAD51C complexes and the RECQ proteins. Public Health Relevance: Our research goal is to understand the complex mechanisms that repair damaged DNA, because loss of genome integrity can lead to cell transformation and cancer development. Our detailed knowledge of DNA repair proteins is also crucial for developing drugs that can be used in combination with radiotherapy or chemotherapy, since the inhibition of DNA damage repair in tumor cells would make them more susceptible to therapy, thus allowing more efficient treatment of cancer. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA130910-01A2
Application #
7529332
Study Section
Radiation Therapeutics and Biology Study Section (RTB)
Program Officer
Pelroy, Richard
Project Start
2008-09-01
Project End
2013-07-31
Budget Start
2008-09-01
Budget End
2009-07-31
Support Year
1
Fiscal Year
2008
Total Cost
$274,730
Indirect Cost
Name
Yale University
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Li, Min; Pokharel, Subhash; Wang, Jiin-Tarng et al. (2015) RECQ5-dependent SUMOylation of DNA topoisomerase I prevents transcription-associated genome instability. Nat Commun 6:6720