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 mechanisms of ICL repair in bacteria and yeast, their processing in mammalian cells is not clearly defined. In the previous funding period, we demonstrated an nucleotide excision repair (NER)-dependent, error-prone repair of triplex-directed psoralen ICLs in mammalian cells. We also found that mismatch repair (MMR) proteins are involved in the response to and repair of psoralen ICLs in an error-free process. Our working hypothesis in this renewal application is that NER and mismatch repair (MMR) proteins interact in the recognition and initial processing of ICLs, while MMR proteins, independently of NER factors, are involved in ICL-induced cell-cycle regulation and apoptosis. The long-term objectives of the proposed research are to elucidate molecular mechanisms involved in the removal of DNA ICLs from the mammalian genome, to identify interactions among proteins from HR, MMR, and NER pathways in doing so, and to determine the roles of these proteins in other cellular responses to these lesions. Specifically we propose to: 1) test the hypothesis that proteins from the NER and MMR pathways interact during recognition and initial processing of ICLs;2) test the proposal that MLH1 functions in cellular checkpoint and apoptosis responses to DNA ICLs;3) target DNA ICLs to specific genomic sites in mutant mammalian cell lines to determine roles for DNA repair and recombination gene products in processing ICLs;and 4) assess the potential of targeted ICLs as antiproliferative therapeutic agents. The results obtained from these studies will provide valuable information to develop improved targeted strategies to control human cancers using ICL-inducing agents.

Public Health Relevance

This Research Project 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 #
5P01CA097175-10
Application #
8606183
Study Section
Special Emphasis Panel (ZCA1-GRB-S)
Project Start
Project End
Budget Start
2014-01-01
Budget End
2014-12-31
Support Year
10
Fiscal Year
2014
Total Cost
$180,277
Indirect Cost
Name
University of Texas MD Anderson Cancer Center
Department
Type
DUNS #
800772139
City
Houston
State
TX
Country
United States
Zip Code
77030
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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
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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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