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- W2912859943 abstract "Abstract The most frequently recurring cancer-associated DNA polymerase ε (Pol ε) mutation is a P286R substitution in the exonuclease domain. While originally proposed to increase genome instability by disrupting exonucleolytic proofreading, the P286R variant was later found to be significantly more pathogenic than Pol ε proofreading deficiency per se . The mechanisms underlying its stronger impact remained unclear. Here we report the crystal structure of the yeast orthologue, Pol ε−P301R, complexed with DNA and an incoming dNTP. Structural changes in the protein are confined to the exonuclease domain, with R301 pointing towards the exonuclease site. Molecular dynamics simulations suggest that R301 interferes with DNA binding to the exonuclease site, an outcome not observed with the exonuclease-inactive Pol ε−D290A,E292A variant lacking the catalytic residues. These results reveal a distinct mechanism of exonuclease inactivation by the P301R substitution and a likely basis for its dramatically higher mutagenic and tumorigenic effects." @default.
- W2912859943 created "2019-02-21" @default.
- W2912859943 creator A5006663720 @default.
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- W2912859943 creator A5062278268 @default.
- W2912859943 creator A5079060690 @default.
- W2912859943 creator A5088789180 @default.
- W2912859943 date "2019-01-22" @default.
- W2912859943 modified "2023-10-15" @default.
- W2912859943 title "Structural consequence of the most frequently recurring cancer-associated substitution in DNA polymerase ε" @default.
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- W2912859943 doi "https://doi.org/10.1038/s41467-018-08114-9" @default.
- W2912859943 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/6342957" @default.
- W2912859943 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/30670696" @default.
- W2912859943 hasPublicationYear "2019" @default.
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