Bypass of the Major Alkylative DNA Lesion by Human DNA Polymerase η

Koag, Myong-Chul; Jung, Hunmin; Kou, Yi; Lee, Seongmin

doi:10.3390/molecules24213928

Bypass of the Major Alkylative DNA Lesion by Human DNA Polymerase η

Journal Article · Thu Oct 31 00:00:00 EDT 2019 · Molecules

DOI:https://doi.org/10.3390/molecules24213928· OSTI ID:1628491

Koag, Myong-Chul ^[1]; ^[2]; ^[2]; ^[2]

Univ. of Texas, Austin, TX (United States). The Division of Chemical Biology and Medicinal Chemistry; DOE/OSTI
Univ. of Texas, Austin, TX (United States). The Division of Chemical Biology and Medicinal Chemistry

A wide range of endogenous and exogenous alkylating agents attack DNA to generate various alkylation adducts. N7-methyl-2-deoxyguanosine (Fm7dG) is the most abundant alkylative DNA lesion. If not repaired, Fm7dG can undergo spontaneous depurination, imidazole ring-opening, or bypass by translesion synthesis DNA polymerases. Human DNA polymerase η (polη) efficiently catalyzes across Fm7dG in vitro, but its structural basis is unknown. Herein, we report a crystal structure of polη in complex with templating Fm7dG and an incoming nonhydrolyzable dCTP analog, where a 2'-fluorine-mediated transition destabilization approach was used to prevent the spontaneous depurination of Fm7dG. The structure showed that polη readily accommodated the Fm7dG:dCTP base pair with little conformational change of protein and DNA. In the catalytic site, Fm7dG and dCTP formed three hydrogen bonds with a Watson–Crick geometry, indicating that the major keto tautomer of Fm7dG is involved in base pairing. The polη-Fm7dG:dCTP structure was essentially identical to the corresponding undamaged structure, which explained the efficient bypass of the major methylated lesion. Overall, the first structure of translesion synthesis DNA polymerase bypassing Fm7dG suggests that in the catalytic site of Y-family DNA polymerases, small N7-alkylguanine adducts may be well tolerated and form the canonical Watson–Crick base pair with dCTP through their keto tautomers.

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:: 1628491

Journal Information:: Molecules, Journal Name: Molecules Journal Issue: 21 Vol. 24; ISSN MOLEFW; ISSN 1420-3049

Publisher:: MDPICopyright Statement

Country of Publication:: United States

Language:: English

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X-ray crystallography
59 BASIC BIOLOGICAL SCIENCES
Biochemistry & Molecular Biology
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N7-methylguanine
translesion synthesis DNA polymerase

Bypass of the Major Alkylative DNA Lesion by Human DNA Polymerase η

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