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Heterozygous colon cancer-associated mutations of SAMHD1 have functional significance
Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics. Umeå University, Faculty of Science and Technology, Department of Chemistry.
Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
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2016 (English)In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 113, no 17, 4723-4728 p.Article in journal (Refereed) Published
Abstract [en]

Even small variations in dNTP concentrations decrease DNA replication fidelity, and this observation prompted us to analyze genomic cancer data for mutations in enzymes involved in dNTP metabolism. We found that sterile alpha motif and histidine-aspartate domain-containing protein 1 (SAMHD1), a deoxyribonucleoside triphosphate triphosphohydrolase that decreases dNTP pools, is frequently mutated in colon cancers, that these mutations negatively affect SAMHD1 activity, and that severalSAMHD1mutations are found in tumors with defective mismatch repair. We show that minor changes in dNTP pools in combination with inactivated mismatch repair dramatically increase mutation rates. Determination of dNTP pools in mouse embryos revealed that inactivation of oneSAMHD1allele is sufficient to elevate dNTP pools. These observations suggest that heterozygous cancer-associatedSAMHD1mutations increase mutation rates in cancer cells.

Place, publisher, year, edition, pages
2016. Vol. 113, no 17, 4723-4728 p.
National Category
Cell and Molecular Biology
Research subject
cellforskning
Identifiers
URN: urn:nbn:se:umu:diva-119232DOI: 10.1073/pnas.1519128113ISI: 000374748400052PubMedID: 27071091OAI: oai:DiVA.org:umu-119232DiVA: diva2:919642
Funder
Knut and Alice Wallenberg FoundationSwedish Cancer SocietySwedish Research Council
Available from: 2016-04-14 Created: 2016-04-14 Last updated: 2016-06-20Bibliographically approved

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Rentoft, MatildaLindell, KristofferTran, PhongChabes, Anna LenaBuckland, RobertWatt, Danielle L.Marjavaara, LisetteNilsson, Anna KarinMelin, BeatriceTrygg, JohanJohansson, ErikChabes, Andrei
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Department of Medical Biochemistry and BiophysicsDepartment of ChemistryDepartment of Radiation Sciences
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Proceedings of the National Academy of Sciences of the United States of America
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