7JK1

Human PrimPol inserting correct dCTP opposite the 8-oxoguanine lesion

Summary for 7JK1

• Entry DOI: 10.2210/pdb7jk1/pdb
• Descriptor: DNA-directed primase/polymerase protein, DNA (5'-D(P*AP*(8OG)P*CP*GP*CP*TP*AP*CP*CP*AP*CP*AP*CP*CP*CP*C)-3'), DNA (5'-D(*GP*GP*TP*GP*TP*GP*GP*TP*AP*GP*CP*G)-3'), ... (8 entities in total)
• Functional Keywords: translesion, dna synthesis, dna replication, dna damage, transferase, transferase-dna complex, transferase/dna
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 6
• Total formula weight: 101179.33

Authors

Rechkoblit, O.,Aggarwal, A.K. (deposition date: 2020-07-27, release date: 2021-06-30, Last modification date: 2023-10-18)

Primary citation

Rechkoblit, O.,Johnson, R.E.,Gupta, Y.K.,Prakash, L.,Prakash, S.,Aggarwal, A.K.
Structural basis of DNA synthesis opposite 8-oxoguanine by human PrimPol primase-polymerase.
Nat Commun, 12:4020-4020, 2021

PubMed 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.

PubMed: 34188055
DOI: 10.1038/s41467-021-24317-z

Experimental method

X-RAY DIFFRACTION (2.62 Å)