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
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;
Department of Medical Biochemistry and Biophysics, Umeå University, Umea SE 901 87, Sweden;
Proc Natl Acad Sci U S A. 2016 Apr 26;113(17):4723-8. doi: 10.1073/pnas.1519128113. Epub 2016 Apr 11.
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.
即使dNTP浓度的微小变化也会降低DNA复制保真度，这一观察结果促使我们分析基因组癌症数据，以寻找参与dNTP代谢的酶的突变情况。我们发现，无菌α基序和含组氨酸-天冬氨酸结构域蛋白1（SAMHD1），一种可减少dNTP库的脱氧核苷三磷酸三磷酸水解酶，在结肠癌中经常发生突变，这些突变对SAMHD1活性产生负面影响，并且在错配修复缺陷的肿瘤中发现了几种SAMHD1突变。我们表明，dNTP库的微小变化与失活的错配修复相结合会显著提高突变率。对小鼠胚胎中dNTP库的测定表明，一个SAMHD1等位基因的失活足以提高dNTP库。这些观察结果表明，与癌症相关的SAMHD1杂合突变会增加癌细胞中的突变率。
