DNA interstrand crosslinks (ICLs) present a formidable block to DNA metabolic processes and must be repaired for cell survival. While much work has been done to define the mechanism(s) of DNA interstrand crosslink repair in bacteria and yeast, very little is known about their repair in mammalian cells. It is has been proposed that both homologous recombination (HR) and nucleotide excision repair pathways are involved in DNA crosslink repair. It is becoming increasingly evident that there is overlap among the DNA repair pathways for certain types of DNA lesions. Our working hypothesis is that a number of proteins already defined as essential in DNA repair mechanisms are also required for efficient HR, or work together with HR in DNA interstrand crosslink processing and removal. The long-term objectives of the proposed research are to elucidate the molecular mechanism(s) involved in the removal of site-specific DNA interstrand crosslinks and complex DNA lesions (psoralen plus UVA radiation and mitomycin C crosslinks directed by triplex formation) from the mammalian genome, to identify interactions among the DNA repair pathways, and to determine the role(s) of homologous recombination, nucleotide excision, and mismatch repair mechanisms in the removal and processing of ICLs and complex DNA lesions. Specifically we propose to: 1) direct sitespecific DNA crosslinks to the genome in normal and recombination-deficient Chinese hamster ovary cells to elucidate the role of recombination in the removal of interstrand crosslinks and complex DNA lesions; 2) determine the mechanism(s) of removal of site-specific DNA interstrand crosslinks and complex DNA lesions directed by triplex-forming oligonucleotides in mammalian cell-free extracts; and 3) identify interactions between proteins involved in DNA repair pathways in the removal of site-specific DNA interstrand crosslinks and complex DNA lesions.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA097175-05
Application #
7591800
Study Section
Subcommittee G - Education (NCI)
Project Start
Project End
Budget Start
2008-04-01
Budget End
2009-03-31
Support Year
5
Fiscal Year
2008
Total Cost
$260,501
Indirect Cost
Name
University of Texas MD Anderson Cancer Center
Department
Type
DUNS #
800772139
City
Houston
State
TX
Country
United States
Zip Code
77030
Tomida, Junya; Takata, Kei-Ichi; Bhetawal, Sarita et al. (2018) FAM35A associates with REV7 and modulates DNA damage responses of normal and BRCA1-defective cells. EMBO J 37:
Klages-Mundt, Naeh L; Li, Lei (2017) Formation and repair of DNA-protein crosslink damage. Sci China Life Sci 60:1065-1076
Malaby, Andrew W; Martin, Sara K; Wood, Richard D et al. (2017) Expression and Structural Analyses of Human DNA Polymerase ? (POLQ). Methods Enzymol 592:103-121
Manandhar, Mandira; Lowery, Megan G; Boulware, Karen S et al. (2017) Transcriptional consequences of XPA disruption in human cell lines. DNA Repair (Amst) 57:76-90
Mukherjee, Anirban; Vasquez, Karen M (2016) Tools to Study the Role of Architectural Protein HMGB1 in the Processing of Helix Distorting, Site-specific DNA Interstrand Crosslinks. J Vis Exp :
Zhang, Xiaoshan; Lu, Xiaoyan; Akhter, Shamima et al. (2016) FANCI is a negative regulator of Akt activation. Cell Cycle 15:1134-43
Mukherjee, Anirban; Vasquez, Karen M (2016) HMGB1 interacts with XPA to facilitate the processing of DNA interstrand crosslinks in human cells. Nucleic Acids Res 44:1151-60
Lange, Sabine S; Tomida, Junya; Boulware, Karen S et al. (2016) The Polymerase Activity of Mammalian DNA Pol ? Is Specifically Required for Cell and Embryonic Viability. PLoS Genet 12:e1005759
Wood, Richard D; Doublié, Sylvie (2016) DNA polymerase ? (POLQ), double-strand break repair, and cancer. DNA Repair (Amst) 44:22-32
Tian, Yanyan; Paramasivam, Manikandan; Ghosal, Gargi et al. (2015) UHRF1 contributes to DNA damage repair as a lesion recognition factor and nuclease scaffold. Cell Rep 10:1957-66

Showing the most recent 10 out of 83 publications