Mechanism of genome instability mediated by human DNA polymerase mu misincorporation.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 34145298.
- Also identified by DOI 10.1038/s41467-021-24096-7 and PMC identifier 8213813.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
Abstract
Pol μ is capable of performing gap-filling repair synthesis in the nonhomologous end joining (NHEJ) pathway. Together with DNA ligase, misincorporation of dGTP opposite the templating T by Pol μ results in a promutagenic T:G mispair, leading to genomic instability. Here, crystal structures and kinetics of Pol μ substituting dGTP for dATP on gapped DNA substrates containing templating T were determined and compared. Pol μ is highly mutagenic on a 2-nt gapped DNA substrate, with T:dGTP base pairing at the 3' end of the gap. Two residues (Lys438 and Gln441) interact with T:dGTP and fine tune the active site microenvironments. The in-crystal misincorporation reaction of Pol μ revealed an unexpected second dGTP in the active site, suggesting its potential mutagenic role among human X family polymerases in NHEJ.
Medical subject headings
- Base Pair Mismatch
- DNA Damage
- DNA End-Joining Repair
- DNA-Directed DNA Polymerase
- Genomic Instability