Heterozygous colon cancer-associated mutations of SAMHD1 have functional significance

Proc Natl Acad Sci U S A. 2016 Apr 26;113(17):4723-8. doi: 10.1073/pnas.1519128113. Epub 2016 Apr 11.

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.

Keywords: DNA replication fidelity; colon cancer; dNTP pools.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Colonic Neoplasms / genetics*
  • DNA Replication
  • DNA, Neoplasm / genetics*
  • Deoxyribonucleotides / genetics*
  • Genetic Predisposition to Disease / genetics
  • Heterozygote
  • Humans
  • Mice
  • Mice, Inbred C57BL
  • Monomeric GTP-Binding Proteins / genetics*
  • Monomeric GTP-Binding Proteins / metabolism*
  • Mutation / genetics*
  • Polymorphism, Single Nucleotide / genetics*
  • SAM Domain and HD Domain-Containing Protein 1

Substances

  • DNA, Neoplasm
  • Deoxyribonucleotides
  • SAM Domain and HD Domain-Containing Protein 1
  • SAMHD1 protein, human
  • Samhd1 protein, mouse
  • Monomeric GTP-Binding Proteins