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

Year: 2021

Type: article

Abstract: 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.

Source: Nature Communications

DOI: 10.1038/s41467-021-24317-z

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

Institutions: Icahn School of Medicine at Mount Sinai, The University of Texas Medical Branch at Galveston, The University of Texas at San Antonio Health Science Center

Language: English

Topic: DNA Repair Mechanisms

Subfield: Molecular Biology

Field: Biochemistry, Genetics and Molecular Biology

Domain: Life Sciences

Open Access status: gold

Estimated APC paid: $5,560

Funders: U.S. Department of Energy, U.S. Department of Health and Human Services, Cancer Prevention and Research Institute of Texas, National Institutes of Health, Office of Science, National Institute of General Medical Sciences, National Center for Research Resources, Argonne National Laboratory

OpenAlex ID: W3175928653