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

Olga Rechkoblit (), Robert E. Johnson, Yogesh K. Gupta, Louise Prakash, Satya Prakash and Aneel K. Aggarwal ()
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Olga Rechkoblit: Icahn School of Medicine at Mount Sinai
Robert E. Johnson: University of Texas Medical Branch
Yogesh K. Gupta: Icahn School of Medicine at Mount Sinai
Louise Prakash: University of Texas Medical Branch
Satya Prakash: University of Texas Medical Branch
Aneel K. Aggarwal: Icahn School of Medicine at Mount Sinai

Nature Communications, 2021, vol. 12, issue 1, 1-11

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-24317-z

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