Structural and Kinetic Analysis of Miscoding Opposite the DNA Adduct 1,N6 -Ethenodeoxyadenosine by Human Translesion DNA Polymerase $η$

Patra, Amritraj; Su, Yan; Zhang, Qianqian; Johnson, Kevin M.; Guengerich, F. Peter; Egli, Martin

doi:10.1074/jbc.M116.732487

Structural and Kinetic Analysis of Miscoding Opposite the DNA Adduct 1,N⁶ -Ethenodeoxyadenosine by Human Translesion DNA Polymerase $$η$$

Journal Article · Mon May 16 00:00:00 EDT 2016 · Journal of Biological Chemistry

DOI:https://doi.org/10.1074/jbc.M116.732487· OSTI ID:1267469

Patra, Amritraj ^[1]; Su, Yan ^[1]; Zhang, Qianqian ^[1]; Johnson, Kevin M. ^[1]; Guengerich, F. Peter ^[1]; Egli, Martin ^[1]

Vanderbilt Univ., Nashville, TN (United States)

1,N⁶-Ethenodeoxyadenosine (1,N⁶-ϵdA) is the major etheno lesion formed in the reaction of DNA with epoxides substituted with good leaving groups (e.g. vinyl chloride epoxide). This lesion is also formed endogenously in DNA from lipid oxidation. Recombinant human DNA polymerase η (hpol η) can replicate oligonucleotide templates containing 1,N⁶-ϵdA. In steady-state kinetic analysis, hpol η preferred to incorporate dATP and dGTP, compared with dTTP. Mass spectral analysis of incorporation products also showed preferred purine (A, G) incorporation and extensive –1 frameshifts, suggesting pairing of the inserted purine and slippage before further replication. Five x-ray crystal structures of hpol η ternary complexes were determined, three at the insertion and two at the extension stage. We report two insertion complexes revealed incoming non-hydrolyzable dATP or dGTP analogs not pairing with but instead in a staggered configuration relative to 1,N⁶-ϵdA in the anti conformation, thus opposite the 5'-T in the template, explaining the proclivity for frameshift misincorporation. In another insertion complex, dTTP was positioned opposite 1,N⁶-ϵdA, and the adduct base was in the syn conformation, with formation of two hydrogen bonds. At the extension stage, with either an incorporated dA or dT opposite 1,N⁶-ϵdA and 2'-deoxythymidine-5'-[(α,β)-imido]triphosphate opposite the 5'-A, the 3'-terminal nucleoside of the primer was disordered, consistent with the tendency not to incorporate dTTP opposite 1,N⁶-ϵdA. Collectively, the results show a preference for purine pairing opposite 1,N⁶-ϵdA and for –1 frameshifts.

View Accepted Manuscript (DOE)

Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22); National Institutes of Health (NIH)

Grant/Contract Number:: AC02-06CH11357

OSTI ID:: 1267469

Journal Information:: Journal of Biological Chemistry, Journal Name: Journal of Biological Chemistry Journal Issue: 27 Vol. 291; ISSN 0021-9258

Publisher:: American Society for Biochemistry and Molecular BiologyCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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