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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.ORCID iD: 0000-0001-5609-6097
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, p. 4723-4728Article 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, p. 4723-4728
National Category
Cell and Molecular Biology
Research subject
cell research
Identifiers
URN: urn:nbn:se:umu:diva-119232DOI: 10.1073/pnas.1519128113ISI: 000374748400052PubMedID: 27071091Scopus ID: 2-s2.0-84964773876OAI: oai:DiVA.org:umu-119232DiVA, id: diva2:919642
Funder
Knut and Alice Wallenberg FoundationSwedish Cancer SocietySwedish Research CouncilAvailable from: 2016-04-14 Created: 2016-04-14 Last updated: 2024-07-02Bibliographically approved
In thesis
1. Pathology of dNTP dysregulation
Open this publication in new window or tab >>Pathology of dNTP dysregulation
2020 (English)Doctoral thesis, comprehensive summary (Other academic)
Alternative title[sv]
Patologier orsakade av dysfunktionell dNTP-reglering
Abstract [en]

Deoxyribonucleoside triphosphates (dNTPs) are precursors for DNA replication and repair. Mammalian cells have two distinct biosynthesis pathways to supply dNTPs: de novo and salvage pathways. These pathways are intimately coordinated to maintain optimal dNTP concentrations throughout different phases of the cell cycle, and perturbations in the production of dNTPs could lead to increased, decreased, or imbalanced dNTP pools. In yeasts, changes in both the level and balance of dNTPs increase mutation rates and genome instability. In mammals, elevated mutation rates and genome instability predispose to numerous diseases, including cancer. However, the correlation of dNTP changes with pathology has not been well established in mammals. In this thesis, I present how we addressed this issue using three separate mouse models – one with an increased dNTP pool, one with a decreased dNTP pool, and one with an imbalanced dNTP pool. To modulate dNTP levels in the mice, we deleted or mutated either sterile alpha motif and histidine-aspartic domain containing protein 1 (SAMHD1) or ribonucleotide reductase (RNR) proteins, which are involved in the salvage and de novo pathways, respectively. In the first model, mouse embryos without the SAMHD1 gene showed a slight increase in dNTP levels. A similar increase in dNTPs conferred moderately elevated mutation rates in cultured cancer cells. In the second model, we created a mouse strain carrying a modified allosteric specificity site in a subunit of RNR. Embryos with a heterozygous mutation had a mildly imbalanced dNTP pool. Heterozygous mutant mice showed a shorter lifespan and increased incidence and earlier onset of cancer. In the third model, the de novo dNTP production was inactivated in cardiac and skeletal muscles through the deletion of a gene encoding RNR. The hearts of knockout pups showed significant depletion of dNTPs, leading to aberrant DNA replication. In addition, knockout pups developed anatomic and histologic cardiac abnormalities and impaired cardiac conduction systems. As a result, they died between two and four weeks after birth. Taken together, our studies provide the first empirical evidence that both the de novo and salvage pathways are essential to keeping the dNTP concentration at an optimal range to prevent mutagenesis, carcinogenesis, and mortality.

Place, publisher, year, edition, pages
Umeå: Umeå University, 2020. p. 43
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 2095
Keywords
dNTP metabolism, DNA replication, mutation rate, cancer, heart development, RNR, SAMHD1, Rrm1, Samhd1
National Category
Natural Sciences
Research subject
Medical Biochemistry
Identifiers
urn:nbn:se:umu:diva-175260 (URN)978-91-7855-346-4 (ISBN)978-91-7855-345-7 (ISBN)
Public defence
2020-10-28, KB.E3.01, byggnad KBC, Umeå University, Umeå, 09:00 (English)
Opponent
Supervisors
Available from: 2020-10-07 Created: 2020-09-23 Last updated: 2024-07-02Bibliographically 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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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
Cell and Molecular Biology

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