OF WORK: We have defined the main mammalian base excision repair (BER) pathways in vitro using purified enzymes and cell extracts, and we have cloned the human and mouse genes for many of the enzymes, expressed the corresponding recombinant proteins in E. coli and insect cells, and prepared cell lines with genetic alterations in each gene. Transgenic mouse models are studied to understand the cellular and tissue requirements for each enzyme. This project includes studies of the cellular role of BER in overall cellular DNA repair, apoptosis, check point control of the cell cycle, mutagenesis, chromosome stability, DNA lesion bypass, cell signaling, DNA replication control, and human and mouse carcinogenesis. In addition, recent studies by several laboratories have suggested that transcription-coupled BER is an important pathway in oxidative damage DNA repair; investigation of this pathway is also underway.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
Intramural Research (Z01)
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U.S. National Inst of Environ Hlth Scis
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Ça?layan, Melike; Wilson, Samuel H (2018) Pol ? dGTP mismatch insertion opposite T coupled with ligation reveals promutagenic DNA repair intermediate. Nat Commun 9:4213
Dai, Da-Peng; Gan, Wei; Hayakawa, Hiroshi et al. (2018) Transcriptional mutagenesis mediated by 8-oxoG induces translational errors in mammalian cells. Proc Natl Acad Sci U S A 115:4218-4222
Oertell, Keriann; Kashemirov, Boris A; Negahbani, Amirsoheil et al. (2018) Probing DNA Base-Dependent Leaving Group Kinetic Effects on the DNA Polymerase Transition State. Biochemistry 57:3925-3933
Horton, Julie K; Stefanick, Donna F; Ça?layan, Melike et al. (2018) XRCC1 phosphorylation affects aprataxin recruitment and DNA deadenylation activity. DNA Repair (Amst) 64:26-33
Çaglayan, Melike; Wilson, Samuel H (2017) Role of DNA polymerase ? oxidized nucleotide insertion in DNA ligation failure. J Radiat Res 58:603-607
Ça?layan, Melike; Horton, Julie K; Dai, Da-Peng et al. (2017) Oxidized nucleotide insertion by pol ? confounds ligation during base excision repair. Nat Commun 8:14045
Horton, Julie K; Stefanick, Donna F; Zhao, Ming-Lang et al. (2017) XRCC1-mediated repair of strand breaks independent of PNKP binding. DNA Repair (Amst) 60:52-63
Prasad, Rajendra; Ça?layan, Melike; Dai, Da-Peng et al. (2017) DNA polymerase ?: A missing link of the base excision repair machinery in mammalian mitochondria. DNA Repair (Amst) 60:77-88
Perera, Lalith; Beard, William A; Pedersen, Lee G et al. (2017) Hiding in Plain Sight: The Bimetallic Magnesium Covalent Bond in Enzyme Active Sites. Inorg Chem 56:313-320
Perera, Lalith; Freudenthal, Bret D; Beard, William A et al. (2017) Revealing the role of the product metal in DNA polymerase ? catalysis. Nucleic Acids Res 45:2736-2745

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