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

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-prime...

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Bibliographic Details
Published in:	Nature communications 2021-06, Vol.12 (1), p.4020-4020, Article 4020
Main Authors:	Rechkoblit, Olga, Johnson, Robert E., Gupta, Yogesh K., Prakash, Louise, Prakash, Satya, Aggarwal, Aneel K.
Format:	Article
Language:	eng
Subjects:	BASIC BIOLOGICAL SCIENCES Crystal structure Damage Deoxyribonucleic acid DNA DNA biosynthesis DNA damage DNA polymerase DNA primase DNA-directed DNA polymerase Insertion Lesions Misalignment Mitochondria Mutagenesis Nuclei (cytology) Primase Structural biology Translesion synthesis X-ray crystallography
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Summary:	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.
ISSN:	2041-1723 2041-1723