title: Endogenous DNA replication stress results in expansion of dNTP pools and a mutator phenotype.
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.
authors.affiliation: Department of Biochemistry and Donnelly Centre, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Marta B
authors.initials: MB
authors.lastname: Davidson
authors.forename: Yuki
authors.initials: Y
authors.lastname: Katou
authors.forename: Andrea
authors.initials: A
authors.lastname: Keszthelyi
authors.forename: Tina L
authors.initials: TL
authors.lastname: Sing
authors.forename: Tian
authors.initials: T
authors.lastname: Xia
authors.forename: Jiongwen
authors.initials: J
authors.lastname: Ou
authors.forename: Jessica A
authors.initials: JA
authors.lastname: Vaisica
authors.forename: Neroshan
authors.initials: N
authors.lastname: Thevakumaran
authors.forename: Lisette
authors.initials: L
authors.lastname: Marjavaara
authors.forename: Chad L
authors.initials: CL
authors.lastname: Myers
authors.forename: Andrei
authors.initials: A
authors.lastname: Chabes
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Shirahige
authors.forename: Grant W
authors.initials: GW
authors.lastname: Brown
mesh_terms: D004249:DNA Damage; D004261:DNA Replication / Q000187:drug effects; D003853:Deoxyribonucleosides / Q000378:metabolism*; D006918:Hydroxyurea / Q000494:pharmacology; D016296:Mutagenesis; D010641:Phenotype; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D003853:Deoxyribonucleosides; D029701:Saccharomyces cerevisiae Proteins; D006918:Hydroxyurea