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
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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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Bacolla, Albino; Temiz, Nuri A; Yi, Ming et al. (2013) Guanine holes are prominent targets for mutation in cancer and inherited disease. PLoS Genet 9:e1003816
Huang, Yaling; Li, Lei (2013) DNA crosslinking damage and cancer - a tale of friend and foe. Transl Cancer Res 2:144-154
Wang, Yucai; Leung, Justin W; Jiang, Yingjun et al. (2013) FANCM and FAAP24 maintain genome stability via cooperative as well as unique functions. Mol Cell 49:997-1009
Leung, Justin Wai Chung; Wang, Yucai; Fong, Ka Wing et al. (2012) Fanconi anemia (FA) binding protein FAAP20 stabilizes FA complementation group A (FANCA) and participates in interstrand cross-link repair. Proc Natl Acad Sci U S A 109:4491-6

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