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

Marta B. Davidson, Yuki Katou, Andrea Keszthelyi, Tina L. Sing, Tian Xia, Jiongwen Ou, Jessica A. Vaisica, Neroshan Thevakumaran, Lisette Marjavaara, Chad L. Myers, Andrei Chabes, Katsuhiko Shirahige, Grant W. Brown

Research output: Contribution to journalArticlepeer-review

71 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)895-907
Number of pages13
JournalEMBO Journal
Volume31
Issue number4
DOIs
StatePublished - Feb 15 2012

Keywords

  • DNA damage
  • DNA replication
  • deoxyribonucleoside triphosphates
  • mutagenesis
  • ribonucleotide reductase

Fingerprint Dive into the research topics of 'Endogenous DNA replication stress results in expansion of dNTP pools and a mutator phenotype'. Together they form a unique fingerprint.

Cite this