Genome of living organisms is intrinsically unstable and subjected to incessant and deleterious damage from within and outside of cells. Fortunately, elaborate DNA repair systems, including the versatile nucleotide excision repair (NER) have evolved to overcome the consequences of genomic instability- a known hallmark of human cancer. Nevertheless, genomic repair is complicated because the DNA lesions must be promptly accessed within the highly condensed chromatin of cell's nucleus. Thus, studies are proposed to extend the scope of our ongoing work on the regulation of NER by incorporating the latest developments in DNA repair and related areas, especially chromatin remodeling. The project is based on the premise that cells rely on specialized molecular apparatus to modify/remodel/rearrange chromatin structure to overcome the barrier presented by repressive chromatin structure and thus allowing the operation of all the DNA templated processes, including DNA repair. The specific hypotheses addressed are: (i) subsequent to damage induction, e.g., by ultraviolet (UV) irradiation, nucleosomes are differentially rearranged at the sites of non-damaged and damaged chromatin, (ii) the slow and fast repair rates of two main UV photolesions, cyclobutane pyrimidine dimers (CPD) and pyrimidine(6-4)pyrimidone photoproducts (6-4PP), are dependent on different chromatin remodeling machineries, (iii) ubiquitin-proteasome pathway (UPS) intimately regulates chromatin remodeling during NER, and (iv) the excision repair outcome is determined by the interplay between DNA damage response and chromatin remodeling. The proposed work will utilize a relevant plethora of state-of-the art technologies to address following inter-related specific objectives: (1) to demonstrate the involvement of histone modifications in the process of NER in mammalian cells, (2) to discern the nucleosome rearrangement in undamaged and damaged chromatin following UV irradiation and its effect on NER factor binding, (3) to show the participation of chromatin remodeling machinery in the repair of CPD and 6-4PP, (4) to delineate the role of UPS related chromatin remodeling in NER of different UV photolesions, and (5) to understand the interplay of checkpoint signaling, chromatin remodeling and NER factor recruitment following UV irradiation. These studies will provide seminal insights into intricate cellular processes that preserve genomic integrity and prevent initiation of human cancers.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Special Emphasis Panel (ZRG1-DIG-F (02))
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Okano, Paul
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Ohio State University
Schools of Medicine
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Zhao, Ran; Han, Chunhua; Eisenhauer, Eric et al. (2014) DNA damage-binding complex recruits HDAC1 to repress Bcl-2 transcription in human ovarian cancer cells. Mol Cancer Res 12:370-80
Han, Chunhua; Zhao, Ran; Kroger, John et al. (2013) Caspase-2 short isoform interacts with membrane-associated cytoskeleton proteins to inhibit apoptosis. PLoS One 8:e67033
Racoma, Ira O; Meisen, Walter Hans; Wang, Qi-En et al. (2013) Thymoquinone inhibits autophagy and induces cathepsin-mediated, caspase-independent cell death in glioblastoma cells. PLoS One 8:e72882
Wang, Qi-En; Han, Chunhua; Zhao, Ran et al. (2013) p38 MAPK- and Akt-mediated p300 phosphorylation regulates its degradation to facilitate nucleotide excision repair. Nucleic Acids Res 41:1722-33
Ray, Alo; Milum, Keisha; Battu, Aruna et al. (2013) NER initiation factors, DDB2 and XPC, regulate UV radiation response by recruiting ATR and ATM kinases to DNA damage sites. DNA Repair (Amst) 12:273-83
Wang, Qi-En; Han, Chunhua; Zhang, Bo et al. (2012) Nucleotide excision repair factor XPC enhances DNA damage-induced apoptosis by downregulating the antiapoptotic short isoform of caspase-2. Cancer Res 72:666-75
Zhu, Qianzheng; Wani, Gulzar; Sharma, Nidhi et al. (2012) Lack of CAK complex accumulation at DNA damage sites in XP-B and XP-B/CS fibroblasts reveals differential regulation of CAK anchoring to core TFIIH by XPB and XPD helicases during nucleotide excision repair. DNA Repair (Amst) 11:942-50
Wang, Qi-En; Milum, Keisha; Han, Chunhua et al. (2011) Differential contributory roles of nucleotide excision and homologous recombination repair for enhancing cisplatin sensitivity in human ovarian cancer cells. Mol Cancer 10:24
Arafa, El-Shaimaa A; Zhu, Qianzheng; Shah, Zubair I et al. (2011) Thymoquinone up-regulates PTEN expression and induces apoptosis in doxorubicin-resistant human breast cancer cells. Mutat Res 706:28-35
Yin, De-Tao; Wang, Qien; Chen, Li et al. (2011) Germline stem cell gene PIWIL2 mediates DNA repair through relaxation of chromatin. PLoS One 6:e27154

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