7jkp

Human PrimPol misinserting dATP opposite the 8-oxoguanine lesion

spinqualitylabelsall models 7jkp, resolution 2.59Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 7jkp is a 6 chain structure with sequence from Homo sapiens and Synthetic construct. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.592Å Ligands: 8OG, CA, DTP, GOL Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease PRIPO_HUMAN The disease is caused by mutations affecting the gene represented in this entry. Function PRIPO_HUMAN DNA primase and DNA polymerase able to initiate de novo DNA synthesis using dNTPs. Shows a high capacity to tolerate DNA damage lesions such as 8oxoG and abasic sites in DNA. Involved in translesion synthesis via its primase activity by mediating uninterrupted fork progression after programmed or damage-induced fork arrest and by reinitiating DNA synthesis after dNTP depletion. Required for mitochondrial DNA (mtDNA) synthesis, suggesting it may be involved in DNA tolerance during the replication of mitochondrial DNA. Has non-overlapping function with POLH. Publication Abstract from PubMed 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. Structural basis of DNA synthesis opposite 8-oxoguanine by human PrimPol primase-polymerase.,Rechkoblit O, Johnson RE, Gupta YK, Prakash L, Prakash S, Aggarwal AK Nat Commun. 2021 Jun 29;12(1):4020. doi: 10.1038/s41467-021-24317-z. PMID:34188055 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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