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

Author

Listed:
  • 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
    University of Texas Health at San Antonio)

  • Louise Prakash

    (University of Texas Medical Branch)

  • Satya Prakash

    (University of Texas Medical Branch)

  • Aneel K. Aggarwal

    (Icahn School of Medicine at Mount Sinai)

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.

Suggested Citation

  • Olga Rechkoblit & Robert E. Johnson & Yogesh K. Gupta & Louise Prakash & Satya Prakash & Aneel K. Aggarwal, 2021. "Structural basis of DNA synthesis opposite 8-oxoguanine by human PrimPol primase-polymerase," Nature Communications, Nature, vol. 12(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-24317-z
    DOI: 10.1038/s41467-021-24317-z
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