Nucleobases within DNA are attacked by reactive oxygen species to produce 7,8-dihydro-8-oxoguanine (oxoG) and 7,8-dihydro-8-oxoadenine (oxoA) as major oxidative lesions. The high mutagenicity of oxoG is attributed to the lesion's ability to adopt syn-oxoG:anti-dA with Watson–Crick-like geometry. Recent studies have revealed that Sulfolobus solfataricus P2 DNA polymerase IV (Dpo4) inserts nucleotide opposite oxoA in an error-prone manner and accommodates syn-oxoA:anti-dGTP with Watson–Crick-like geometry, highlighting a promutagenic nature of oxoA. To gain further insights into the bypass of oxoA by Dpo4, we have conducted kinetic and structural studies of Dpo4 extending oxoA:dT and oxoA:dG by incorporating dATP opposite templating dT. The extension past oxoA:dG was ∼5-fold less efficient than that past oxoA:dT. Structural studies revealed that Dpo4 accommodated dT:dATP base pair past anti-oxoA:dT with little structural distortion. In the Dpo4-oxoA:dG extension structure, oxoA was in an anti conformation and did not form hydrogen bonds with the primer terminus base. Unexpectedely, the dG opposite oxoA exited the primer terminus site and resided in an extrahelical site, where it engaged in minor groove contacts to the two immediate upstream bases. The extrahelical dG conformation appears to be induced by the stabilization of anti-oxoA conformation via bifurcated hydrogen bonds with Arg332. This unprecedented structure suggests that Dpo4 may use Arg332 to sense 8-oxopurines at the primer terminus site and slow the extension from the mismatch by promoting anti conformation of 8-oxopurines.
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May 2021
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In this issue Samantha and colleagues (pp. 1749–1767) provide insights into the underlying mechanism that governs the recognition of myo-inositol by TNYR SaPLD. The image shows an overlay of the loop conformations of four different structures. The unliganded TNYR structure is coloured magenta, in teal is the structure of the H168A mutant bound to PA, in green is the WT unliganded structure and in grey is the TNYR structure bound to phosphate. Image courtesy of Alice Vrielink.
Research Article|
May 10 2021
Insights into the mismatch discrimination mechanism of Y-family DNA polymerase Dpo4
Hunmin Jung;
Hunmin Jung
Conceptualization, Data curation, Software, Formal analysis, Investigation, Visualization, Methodology, Writing - original draft, Writing - review & editing
The Division of Chemical Biology and Medicinal Chemistry, College of Pharmacy, The University of Texas at Austin, Austin, Texas 78712, U.S.A.
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Seongmin Lee
Conceptualization, Resources, Supervision, Funding acquisition, Validation, Investigation, Visualization, Writing - original draft, Project administration, Writing - review & editing
The Division of Chemical Biology and Medicinal Chemistry, College of Pharmacy, The University of Texas at Austin, Austin, Texas 78712, U.S.A.
Correspondence: Seongmin Lee (SeongminLee@austin.utexas.edu)
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Publisher: Portland Press Ltd
Received:
March 09 2021
Revision Received:
April 20 2021
Accepted:
April 21 2021
Accepted Manuscript online:
April 21 2021
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© 2021 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society
2021
Biochem J (2021) 478 (9): 1769–1781.
Article history
Received:
March 09 2021
Revision Received:
April 20 2021
Accepted:
April 21 2021
Accepted Manuscript online:
April 21 2021
Citation
Hunmin Jung, Seongmin Lee; Insights into the mismatch discrimination mechanism of Y-family DNA polymerase Dpo4. Biochem J 14 May 2021; 478 (9): 1769–1781. doi: https://doi.org/10.1042/BCJ20210162
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