Complex DNA lesions such DNA interstrand cross-links and triplehelix structures are functionally disruptive to the mammalian genome and pose unique challenges to the DNA repair system. It is most likely that repair of complex lesions involves cooperative actions of different DNA repair pathways such as homologous recombinational repair, excision repair, and mismatch repair. Our proposed program project will conduct comprehensive investigations on the processing of complex DNA lesions via molecular biology, genetics, and biochemical approaches. The Protein Factor and DNA Substrate (PPDS) Core will be responsible for the production of reagents used by each project and to establish procedures for generating these reagents. By streamlining the production of critical reagents such as protein factors, antibody, and DNA substrates, each project PI will gain additional time on experimentation and the results yielded from each project will be analogous and reliable. Specifically, the PPDS core will accomplish three service-related aims. 1. Preparation of recombinant DNA constructs for in vivo recombination studies, and for the purpose of producing recombinant proteins for biochemical studies and the generation of antibodies. 2. Fractionation of native proteins from mammalian extracts and purification of specific protein targets. 3. Production and quality control of site- and lesion-specific DNA substrates.

Public Health Relevance

This (Research Project/Core) is part of a multicomponent Program Project with the theme of understanding the processing of complex DNA damage by mammalian cells. The significance to human health is to generate new knowledge and paradigms for modeling DNA repair of DNA interstrand crosslinks (ICLs), to improve therapy using ICL-inducing compounds, and to identify new therapeutic targets for cancer treatment.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
2P01CA097175-06A1
Application #
7781977
Study Section
Special Emphasis Panel (ZCA1-GRB-S (O1))
Project Start
2010-02-01
Project End
2014-12-31
Budget Start
2010-02-01
Budget End
2010-12-31
Support Year
6
Fiscal Year
2010
Total Cost
$143,201
Indirect Cost
Name
University of Texas MD Anderson Cancer Center
Department
Type
DUNS #
800772139
City
Houston
State
TX
Country
United States
Zip Code
77030
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
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
Klages-Mundt, Naeh L; Li, Lei (2017) Formation and repair of DNA-protein crosslink damage. Sci China Life Sci 60:1065-1076
Zhang, Xiaoshan; Lu, Xiaoyan; Akhter, Shamima et al. (2016) FANCI is a negative regulator of Akt activation. Cell Cycle 15:1134-43
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
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
Wood, Richard D; DoubliƩ, 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
Manandhar, Mandira; Boulware, Karen S; Wood, Richard D (2015) The ERCC1 and ERCC4 (XPF) genes and gene products. Gene 569:153-61
Zahn, Karl E; Averill, April M; Aller, Pierre et al. (2015) Human DNA polymerase ? grasps the primer terminus to mediate DNA repair. Nat Struct Mol Biol 22:304-11

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