Nature Communications: Structural basis of DNA synthesis opposite 8-oxoguanine by human PrimPol primase-polymerase (Gupta)
Olga Rechkoblit, Robert E. Johnson, Yogesh K. Gupta, Louise Prakash, Satya Prakash & Aneel K. Aggarwal
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 a 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 the 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.