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Endogenous DNA replication stress results in expansion of dNTP pools and a mutator phenotype.

The integrity of the genome depends on diverse pathways that regulate DNA metabolism. Defects in these pathways result in genome instability, a hallmark of cancer. Deletion of ELG1 in budding yeast, when combined with hypomorphic alleles of PCNA results in spontaneous DNA damage during S phase that elicits upregulation of ribonucleotide reductase (RNR) activity. Increased RNR activity leads to a dramatic expansion of deoxyribonucleotide (dNTP) pools in G1 that allows cells to synthesize significant fractions of the genome in the presence of hydroxyurea in the subsequent S phase. Consistent with the recognized correlation between dNTP levels and spontaneous mutation, compromising ELG1 and PCNA results in a significant increase in mutation rates. Deletion of distinct genome stability genes RAD54, RAD55, and TSA1 also results in increased dNTP levels and mutagenesis, suggesting that this is a general phenomenon. Together, our data point to a vicious circle in which mutations in gatekeeper genes give rise to genomic instability during S phase, inducing expansion of the dNTP pool, which in turn results in high levels of spontaneous mutagenesis.

Pubmed ID: 22234187

Authors

  • Davidson MB
  • Katou Y
  • Keszthelyi A
  • Sing TL
  • Xia T
  • Ou J
  • Vaisica JA
  • Thevakumaran N
  • Marjavaara L
  • Myers CL
  • Chabes A
  • Shirahige K
  • Brown GW

Journal

The EMBO journal

Publication Data

February 15, 2012

Associated Grants

  • Agency: NHGRI NIH HHS, Id: 1R01HG005084-01A1
  • Agency: NHGRI NIH HHS, Id: 1R01HG005853-01
  • Agency: Canadian Institutes of Health Research, Id: MOP79368
  • Agency: NHGRI NIH HHS, Id: R01 HG005853

Mesh Terms

  • DNA Damage
  • DNA Replication
  • Deoxyribonucleosides
  • Hydroxyurea
  • Mutagenesis
  • Phenotype
  • Saccharomyces cerevisiae
  • Saccharomyces cerevisiae Proteins