Structural consequence of the most frequently recurring cancer-associated substitution in DNA polymerase ε View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2019-12

AUTHORS

Vimal Parkash, Yashraj Kulkarni, Josy ter Beek, Polina V. Shcherbakova, Shina Caroline Lynn Kamerlin, Erik Johansson

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. More... »

PAGES

373

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/s41467-018-08114-9

DOI

http://dx.doi.org/10.1038/s41467-018-08114-9

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1111593701

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/30670696


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