umu.sePublications
Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
A recurrent cancer-associated substitution in DNA polymerase ε produces a hyperactive enzyme
Show others and affiliations
2019 (English)In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 10, article id 374Article in journal (Refereed) Published
Abstract [en]

Alterations in the exonuclease domain of DNA polymerase ε (Polε) cause ultramutated tumors. Severe mutator effects of the most common variant, Polε-P286R, modeled in yeast suggested that its pathogenicity involves yet unknown mechanisms beyond simple proofreading deficiency. We show that, despite producing a catastrophic amount of replication errors in vivo, the yeast Polε-P286R analog retains partial exonuclease activity and is more accurate than exonuclease-dead Polε. The major consequence of the arginine substitution is a dramatically increased DNA polymerase activity. This is manifested as a superior ability to copy synthetic and natural templates, extend mismatched primer termini, and bypass secondary DNA structures. We discuss a model wherein the cancer-associated substitution limits access of the 3'-terminus to the exonuclease site and promotes binding at the polymerase site, thus stimulating polymerization. We propose that the ultramutator effect results from increased polymerase activity amplifying the contribution of Polε errors to the genomic mutation rate.

Place, publisher, year, edition, pages
Nature Publishing Group, 2019. Vol. 10, article id 374
National Category
Cell and Molecular Biology
Identifiers
URN: urn:nbn:se:umu:diva-155817DOI: 10.1038/s41467-018-08145-2ISI: 000456286400002PubMedID: 30670691OAI: oai:DiVA.org:umu-155817DiVA, id: diva2:1283191
Funder
NIH (National Institute of Health), ES015869Swedish Cancer SocietySwedish Research CouncilAvailable from: 2019-01-28 Created: 2019-01-28 Last updated: 2019-02-26Bibliographically approved

Open Access in DiVA

fulltext(3802 kB)52 downloads
File information
File name FULLTEXT01.pdfFile size 3802 kBChecksum SHA-512
6f0142cc8e4025049f94795731b8a9e4fb0763b30c6914d35f5b760650b4df945a31d4a754035ab67627bd9a95563d39d40b2fc26e6ef852523ab413a743973d
Type fulltextMimetype application/pdf

Other links

Publisher's full textPubMed

Authority records BETA

Sharma, SushmaChabes, Andrei

Search in DiVA

By author/editor
Sharma, SushmaChabes, Andrei
By organisation
Department of Medical Biochemistry and BiophysicsMolecular Infection Medicine Sweden (MIMS)
In the same journal
Nature Communications
Cell and Molecular Biology

Search outside of DiVA

GoogleGoogle Scholar
Total: 52 downloads
The number of downloads is the sum of all downloads of full texts. It may include eg previous versions that are now no longer available

doi
pubmed
urn-nbn

Altmetric score

doi
pubmed
urn-nbn
Total: 289 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf