title: Heterozygous colon cancer-associated mutations of SAMHD1 have functional significance.
abstract: 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 several SAMHD1 mutations 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 one SAMHD1 allele is sufficient to elevate dNTP pools. These observations suggest that heterozygous cancer-associated SAMHD1 mutations increase mutation rates in cancer cells.
authors.affiliation: Computational Life Science Cluster, Department of Chemistry, Umeå University, Umea SE 901 87, Sweden; Department of Medical Biochemistry and Biophysics, Umeå University, Umea SE 901 87, Sweden;
authors.forename: Matilda
authors.initials: M
authors.lastname: Rentoft
authors.affiliation: Department of Medical Biochemistry and Biophysics, Umeå University, Umea SE 901 87, Sweden;
authors.forename: Kristoffer
authors.initials: K
authors.lastname: Lindell
authors.affiliation: Department of Medical Biochemistry and Biophysics, Umeå University, Umea SE 901 87, Sweden;
authors.forename: Phong
authors.initials: P
authors.lastname: Tran
authors.affiliation: Department of Medical Biochemistry and Biophysics, Umeå University, Umea SE 901 87, Sweden;
authors.forename: Anna Lena
authors.initials: AL
authors.lastname: Chabes
authors.affiliation: Department of Medical Biochemistry and Biophysics, Umeå University, Umea SE 901 87, Sweden;
authors.forename: Robert J
authors.identifier: http://orcid.org/0000-0001-9749-5422
authors.initials: RJ
authors.lastname: Buckland
authors.affiliation: Department of Medical Biochemistry and Biophysics, Umeå University, Umea SE 901 87, Sweden;
authors.forename: Danielle L
authors.initials: DL
authors.lastname: Watt
authors.affiliation: Department of Medical Biochemistry and Biophysics, Umeå University, Umea SE 901 87, Sweden;
authors.forename: Lisette
authors.initials: L
authors.lastname: Marjavaara
authors.affiliation: Department of Medical Biochemistry and Biophysics, Umeå University, Umea SE 901 87, Sweden;
authors.forename: Anna Karin
authors.initials: AK
authors.lastname: Nilsson
authors.affiliation: Department of Radiation Sciences, Umeå University, Umea SE 901 87, Sweden.
authors.forename: Beatrice
authors.initials: B
authors.lastname: Melin
authors.affiliation: Computational Life Science Cluster, Department of Chemistry, Umeå University, Umea SE 901 87, Sweden;
authors.forename: Johan
authors.initials: J
authors.lastname: Trygg
authors.affiliation: Department of Medical Biochemistry and Biophysics, Umeå University, Umea SE 901 87, Sweden;
authors.forename: Erik
authors.initials: E
authors.lastname: Johansson
authors.affiliation: Department of Medical Biochemistry and Biophysics, Umeå University, Umea SE 901 87, Sweden; andrei.chabes@umu.se.
authors.forename: Andrei
authors.identifier: http://orcid.org/0000-0003-1708-8259
authors.initials: A
authors.lastname: Chabes
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000235:genetics*; D004261:DNA Replication; D004273:DNA, Neoplasm / Q000235:genetics*; D003854:Deoxyribonucleotides / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006579:Heterozygote; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D020559:Monomeric GTP-Binding Proteins / Q000235:genetics* / Q000378:metabolism*; D009154:Mutation / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D000076106:SAM Domain and HD Domain-Containing Protein 1
chemical_list: D004273:DNA, Neoplasm; D003854:Deoxyribonucleotides; D000076106:SAM Domain and HD Domain-Containing Protein 1; C484280:SAMHD1 protein, human; C484281:Samhd1 protein, mouse; D020559:Monomeric GTP-Binding Proteins
keywords: DNA replication fidelity; colon cancer; dNTP pools