The mechanisms by which complex lesions, particularly interstrand cross-links (ICLs), are removed or repaired in mammalian cells are poorly understood despite the importance to human health of compounds that induce these lesions. These agents, present in foodstuffs and produced as byproducts of mammalian metabolism, are highly toxic and mutagenic. Conversely, some of these drugs are also employed as highly active anti-tumor agents. The long term objectives of this application, involving four highly integrated projects and three cores, aim to elucidate the molecular mechanisms of repair of ICLs with the anticipation that the knowledge gained from these studies will be of significant value to understanding both the etiology of tumorigenesis and the enhancement of chemotherapeutic regimens. This proposed dissection of the mechanisms of ICL repair will encompass both mutagenic and non-mutagenic pathways, as well as the complete process of repair from lesion recognition to the final stages of restoration of helical integrity. Biochemical, molecular, and genetic approaches will be employed to elucidate of [sic] the mechanistic details of the multiple pathways of ICL repair. In addition, another objective of this application is to explore potential uses of ICL inducing compounds as a methodology to enhance recombination and mutagenesis in mammalian cells. Specifically, the use of triplex technology will be employed to direct ICLs to a particular genetic target. These approaches have excellent potential to yield useful technical and therapeutic advances in genetic manipulation.

Public Health Relevance

This Project Summary describes 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 #
5P01CA097175-09
Application #
8403930
Study Section
Special Emphasis Panel (ZCA1-GRB-S (O1))
Program Officer
Okano, Paul
Project Start
2002-07-01
Project End
2014-12-31
Budget Start
2013-01-01
Budget End
2013-12-31
Support Year
9
Fiscal Year
2013
Total Cost
$1,455,566
Indirect Cost
$508,055
Name
University of Texas MD Anderson Cancer Center
Department
Genetics
Type
Other Domestic Higher Education
DUNS #
800772139
City
Houston
State
TX
Country
United States
Zip Code
77030
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 ζ Is Specifically Required for Cell and Embryonic Viability. PLoS Genet 12:e1005759
Wood, Richard D; Doublié, Sylvie (2016) DNA polymerase θ (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
Tomida, Junya; Takata, Kei-ichi; Lange, Sabine S et al. (2015) REV7 is essential for DNA damage tolerance via two REV3L binding sites in mammalian DNA polymerase ζ. Nucleic Acids Res 43:1000-11
Zahn, Karl E; Averill, April M; Aller, Pierre et al. (2015) Human DNA polymerase θ grasps the primer terminus to mediate DNA repair. Nat Struct Mol Biol 22:304-11
Takata, Kei-Ichi; Tomida, Junya; Reh, Shelley et al. (2015) Conserved overlapping gene arrangement, restricted expression, and biochemical activities of DNA polymerase ν (POLN). J Biol Chem 290:24278-93
Manandhar, Mandira; Boulware, Karen S; Wood, Richard D (2015) The ERCC1 and ERCC4 (XPF) genes and gene products. Gene 569:153-61
Smith, Stephanie; Fox, Jennifer; Mejia, Marco et al. (2014) Histone deacetylase inhibitors selectively target homology dependent DNA repair defective cells and elevate non-homologous endjoining activity. PLoS One 9:e87203

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