DNA tennplates for transcription are continuously damaged by extrinsic factors such as radiation and chemical agents, as well as by products of endogenous metabolic processes. Maintenance of DNA integrity and high fidelity in transcription are crucial for life processes. DNA damage impairs transcription and triggers a variety of cellular responses, including DNA repair pathways, signaling pathways that activate cell cycle checkpoints, apoptosis, transcription, and chromatin remodeling. Defects in DNA repair or the processing of DNA damage can lead to cancer or other human diseases. It is inevitable for RNA polymerases to encounter DNA damage during transcription. Certain types of DNA lesions allow RNA polymerase bypass, while others completely block transcription. RNA polymerase 11 (pol II) bypass frequently results in mutagenesis at RNA, generating mutant proteins. In contrast, arrest of pol II by DNA lesions signals a specific DNA repair pathway to correct the damage and maintain the integrity ofthe DNA. The goal of my research is to understand the mechanisms of these cellular DNA damage processing pathways through an integrated multidisciplinary combination of chemical, structural, biochemical, and molecular biological methods.

Public Health Relevance

This knowledge will provide us strutural insights for transcriptional fidelity control, DNA damage recognition and DNA repair. In addition, this konowledge will have implications for rational drug design for cancer and other transcription related human diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Transition Award (R00)
Project #
5R00GM085136-05
Application #
8209081
Study Section
Special Emphasis Panel (NSS)
Program Officer
Flicker, Paula F
Project Start
2008-07-01
Project End
2012-12-31
Budget Start
2012-01-01
Budget End
2012-12-31
Support Year
5
Fiscal Year
2012
Total Cost
$246,510
Indirect Cost
$71,591
Name
University of California San Diego
Department
None
Type
Schools of Pharmacy
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Xu, Liang; Chen, Ying-Chu; Nakajima, Satoshi et al. (2014) A Chemical Probe Targets DNA 5-Formylcytosine Sites and Inhibits TDG Excision, Polymerases Bypass, and Gene Expression. Chem Sci 5:567-574
Kellinger, Matthew W; Ulrich, Sebastien; Chong, Jenny et al. (2012) Dissecting chemical interactions governing RNA polymerase II transcriptional fidelity. J Am Chem Soc 134:8231-40
Liu, Xin; Bushnell, David A; Wang, Dong et al. (2010) Structure of an RNA polymerase II-TFIIB complex and the transcription initiation mechanism. Science 327:206-9