Heterozygous colon cancer-associated mutations of SAMHD1 have functional significance
Even small variations in dNTP concentrations decrease DNA replication fidelity, and this observation prompted us to analyze genomic cancer data formutations in enzymes involved in dNTP metabolism. We found that sterile alpha motif and histidine-aspartate domain-containing protein 1 (SAMHD1), a deoxy...
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| Veröffentlicht in: | Proceedings of the National Academy of Sciences - PNAS 2016-04, Vol.113 (17), p.4723-4728 |
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| container_title | Proceedings of the National Academy of Sciences - PNAS |
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| creator | Rentoft, Matilda Lindell, Kristoffer Tran, Phong Chabes, Anna Lena Buckland, Robert J. Watt, Danielle L. Marjavaara, Lisette Nilsson, Anna Karin Melin, Beatrice Trygg, Johan Johansson, Erik Chabes, Andrei |
| description | Even small variations in dNTP concentrations decrease DNA replication fidelity, and this observation prompted us to analyze genomic cancer data formutations 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. |
| doi_str_mv | 10.1073/pnas.1519128113 |
| format | Article |
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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.</description><identifier>ISSN: 0027-8424</identifier><identifier>ISSN: 1091-6490</identifier><identifier>EISSN: 1091-6490</identifier><identifier>DOI: 10.1073/pnas.1519128113</identifier><identifier>PMID: 27071091</identifier><language>eng</language><publisher>United States: National Academy of Sciences</publisher><subject>Animals ; Biological Sciences ; Cell Line, Tumor ; cell research ; cellforskning ; Colonic Neoplasms - genetics ; Colorectal cancer ; Deoxyribonucleic acid ; Deoxyribonucleotides - genetics ; DNA ; DNA Replication ; DNA, Neoplasm - genetics ; Enzymes ; Genetic Predisposition to Disease - genetics ; Heterozygote ; Humans ; Inactivation ; Metabolism ; Mice ; Mice, Inbred C57BL ; Monomeric GTP-Binding Proteins - genetics ; Monomeric GTP-Binding Proteins - metabolism ; Mutation ; Mutation - genetics ; Polymorphism, Single Nucleotide - genetics ; SAM Domain and HD Domain-Containing Protein 1 ; Tumors</subject><ispartof>Proceedings of the National Academy of Sciences - PNAS, 2016-04, Vol.113 (17), p.4723-4728</ispartof><rights>Volumes 1–89 and 106–113, copyright as a collective work only; author(s) retains copyright to individual articles</rights><rights>Copyright National Academy of Sciences Apr 26, 2016</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c505t-106fbefa668f48172471ab763b92ed1abf3dc3a0449aee5fcf52e65262fc77563</citedby><cites>FETCH-LOGICAL-c505t-106fbefa668f48172471ab763b92ed1abf3dc3a0449aee5fcf52e65262fc77563</cites><orcidid>0000-0003-1708-8259 ; 0000-0001-9749-5422</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Uhttp://www.pnas.org/content/113/17.cover.gif</thumbnail><linktopdf>$$Uhttps://www.jstor.org/stable/pdf/26469416$$EPDF$$P50$$Gjstor$$H</linktopdf><linktohtml>$$Uhttps://www.jstor.org/stable/26469416$$EHTML$$P50$$Gjstor$$H</linktohtml><link.rule.ids>230,314,550,723,776,780,799,881,27903,27904,53770,53772,57996,58229</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/27071091$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttps://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-119232$$DView record from Swedish Publication Index$$Hfree_for_read</backlink></links><search><creatorcontrib>Rentoft, Matilda</creatorcontrib><creatorcontrib>Lindell, Kristoffer</creatorcontrib><creatorcontrib>Tran, Phong</creatorcontrib><creatorcontrib>Chabes, Anna Lena</creatorcontrib><creatorcontrib>Buckland, Robert J.</creatorcontrib><creatorcontrib>Watt, Danielle L.</creatorcontrib><creatorcontrib>Marjavaara, Lisette</creatorcontrib><creatorcontrib>Nilsson, Anna Karin</creatorcontrib><creatorcontrib>Melin, Beatrice</creatorcontrib><creatorcontrib>Trygg, Johan</creatorcontrib><creatorcontrib>Johansson, Erik</creatorcontrib><creatorcontrib>Chabes, Andrei</creatorcontrib><title>Heterozygous colon cancer-associated mutations of SAMHD1 have functional significance</title><title>Proceedings of the National Academy of Sciences - PNAS</title><addtitle>Proc Natl Acad Sci U S A</addtitle><description>Even small variations in dNTP concentrations decrease DNA replication fidelity, and this observation prompted us to analyze genomic cancer data formutations 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. 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| subjects | Animals Biological Sciences Cell Line, Tumor cell research cellforskning Colonic Neoplasms - genetics Colorectal cancer Deoxyribonucleic acid Deoxyribonucleotides - genetics DNA DNA Replication DNA, Neoplasm - genetics Enzymes Genetic Predisposition to Disease - genetics Heterozygote Humans Inactivation Metabolism Mice Mice, Inbred C57BL Monomeric GTP-Binding Proteins - genetics Monomeric GTP-Binding Proteins - metabolism Mutation Mutation - genetics Polymorphism, Single Nucleotide - genetics SAM Domain and HD Domain-Containing Protein 1 Tumors |
| title | Heterozygous colon cancer-associated mutations of SAMHD1 have functional significance |
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