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Endogenous DNA replication stress results in expansion of dNTP pools and a mutator phenotype
Author(s) -
Davidson Marta B,
Katou Yuki,
Keszthelyi Andrea,
Sing Tina L,
Xia Tian,
Ou Jiongwen,
Vaisica Jessica A,
Thevakumaran Neroshan,
Marjavaara Lisette,
Myers Chad L,
Chabes Andrei,
Shirahige Katsuhiko,
Brown Grant W
Publication year - 2012
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1038/emboj.2011.485
Subject(s) - biology , genetics , dna replication , phenotype , endogeny , dna , replication (statistics) , gene , virology , endocrinology
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.