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.
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.
|Walmacq, Celine; Wang, Lanfeng; Chong, Jenny et al. (2015) Mechanism of RNA polymerase II bypass of oxidative cyclopurine DNA lesions. Proc Natl Acad Sci U S A 112:E410-9|
|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|
|Wang, Lanfeng; Limbo, Oliver; Fei, Jia et al. (2014) Regulation of the Rhp26ERCC6/CSB chromatin remodeler by a novel conserved leucine latch motif. Proc Natl Acad Sci U S A 111:18566-71|
|Zhang, Su; Wang, Dong (2013) Understanding the Molecular Basis of RNA Polymerase II Transcription. Isr J Chem 53:|
|Kellinger, Matthew W; Park, Ga Young; Chong, Jenny et al. (2013) Effect of a monofunctional phenanthriplatin-DNA adduct on RNA polymerase II transcriptional fidelity and translesion synthesis. J Am Chem Soc 135:13054-61|
|Kellinger, Matthew W; Song, Chun-Xiao; Chong, Jenny et al. (2012) 5-formylcytosine and 5-carboxylcytosine reduce the rate and substrate specificity of RNA polymerase II transcription. Nat Struct Mol Biol 19:831-3|
|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|
|Wang, Dong; Zhu, Guangyu; Huang, Xuhui et al. (2010) X-ray structure and mechanism of RNA polymerase II stalled at an antineoplastic monofunctional platinum-DNA adduct. Proc Natl Acad Sci U S A 107:9584-9|
|Huang, Xuhui; Wang, Dong; Weiss, Dahlia R et al. (2010) RNA polymerase II trigger loop residues stabilize and position the incoming nucleotide triphosphate in transcription. Proc Natl Acad Sci U S A 107:15745-50|