Structural basis of DNA synthesis opposite 8-oxoguanine by human PrimPol primase-polymerase

Rechkoblit, Olga; Johnson, Robert E.; Gupta, Yogesh K.; Prakash, Louise; Prakash, Satya; Aggarwal, Aneel K.

doi:10.1038/s41467-021-24317-z

Title: Structural basis of DNA synthesis opposite 8-oxoguanine by human PrimPol primase-polymerase

Journal Article · Tue Jun 29 00:00:00 EDT 2021 · Nature Communications

DOI:https://doi.org/10.1038/s41467-021-24317-z· OSTI ID:1810833

^[1]; Johnson, Robert E. ^[2];

^[3]; Prakash, Louise ^[2]; Prakash, Satya ^[2];

^[1]

Icahn School of Medicine at Mount Sinai, New York, NY (United States)
Univ. of Texas Medical Branch, Galveston, TX (United States)
Icahn School of Medicine at Mount Sinai, New York, NY (United States); Univ. of Texas Health at San Antonio, TX (United States)

PrimPol is a human DNA polymerase-primase that localizes to mitochondria and nucleus and bypasses the major oxidative lesion 7,8-dihydro-8-oxoguanine (oxoG) via translesion synthesis, in mostly error-free manner. We present structures of PrimPol insertion complexes with a DNA template-primer and correct dCTP or erroneous dATP opposite the lesion, as well as extension complexes with C or A as a 3'–terminal primer base. We show that during the insertion of C and extension from it, the active site is unperturbed, reflecting the readiness of PrimPol to accommodate oxoG(anti). The misinsertion of A opposite oxoG(syn) also does not alter the active site, and is likely less favorable due to lower thermodynamic stability of the oxoG(syn)•A base-pair. During the extension step, oxoG(syn) induces an opening of its base-pair with A or misalignment of the 3'-A primer terminus. Together, the structures show how PrimPol accurately synthesizes DNA opposite oxidatively damaged DNA in human cells.

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

Sponsoring Organization:: USDOE Office of Science (SC); National Institutes of Health (NIH)

Grant/Contract Number:: AC02-06CH11357; R35-GM131780; R01 GM126087; S10 RR029205

OSTI ID:: 1810833

Journal Information:: Nature Communications, Vol. 12, Issue 1; ISSN 2041-1723

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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Title: Structural basis of DNA synthesis opposite 8-oxoguanine by human PrimPol primase-polymerase

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