Transition-state destabilization reveals how human DNA polymerase β proceeds across the chemically unstable lesion N7-methylguanine

Koag, Myong-Chul; Kou, Yi; Ouzon-Shubeita, Hala; Lee, Seongmin

doi:10.1093/nar/gku554

Transition-state destabilization reveals how human DNA polymerase β proceeds across the chemically unstable lesion N7-methylguanine

Journal Article · Wed Jun 25 00:00:00 EDT 2014 · Nucleic Acids Research

DOI:https://doi.org/10.1093/nar/gku554· OSTI ID:1625539

Koag, Myong-Chul ^[1]; Kou, Yi ^[2]; Ouzon-Shubeita, Hala ^[2]; Lee, Seongmin ^[2]

Univ. of Texas, Austin, TX (United States). College of Pharmacy. Division of Medicinal Chemistry; DOE/OSTI
Univ. of Texas, Austin, TX (United States). College of Pharmacy. Division of Medicinal Chemistry

N7-Methyl-2 -deoxyguanosine (m7dG) is the predominant lesion formed by methylating agents. A systematic investigation on the effect of m7dG on DNA replication has been difficult due to the chemical instability of m7dG. To gain insights into the m7dG effect, we employed a 2 -fluorine-mediated transitionstate destabilzation strategy. Specifically, we determined kinetic parameters for dCTP insertion opposite a chemically stable m7dG analogue, 2 -fluorom7dG (Fm7dG), by human DNA polymerase (pol) and solved three X-ray structures of pol in complex with the templating Fm7dG paired with incoming dCTP or dTTP analogues. The kinetic studies reveal that the templating Fm7dG slows pol catalysis ~300-fold, suggesting that m7dG in genomic DNA may impede replication by some DNA polymerases. The structural analysis reveals that Fm7dG forms a canonical Watson–Crick base pair with dCTP, but metal ion coordination is suboptimal for catalysis in the pol-Fm7dG:dCTP complex, which partially explains the slow insertion of dCTP opposite Fm7dG by pol. In addition, the pol-Fm7dG:dTTP structure shows open protein conformations and staggered base pair conformations, indicating that N7- methylation of dG does not promote a promutagenic replication. Overall, the first systematic studies on the effect of m7dG on DNA replication reveal that pol catalysis across m7dG is slow, yet highly accurate.

View Accepted Manuscript (DOE)

Research Organization:: Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)

Sponsoring Organization:: USDOE Office of Science (SC), Biological and Environmental Research (BER). Biological Systems Science Division

Grant/Contract Number:: AC02-05CH11231

OSTI ID:: 1625539

Journal Information:: Nucleic Acids Research, Journal Name: Nucleic Acids Research Journal Issue: 13 Vol. 42; ISSN 0305-1048

Publisher:: Oxford University PressCopyright Statement

Country of Publication:: United States

Language:: English

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