Endogenous DNA replication stress results in expansion of dNTP pools and a mutator phenotype.
EMBO J
; 31(4): 895-907, 2012 Feb 15.
Article
em En
| MEDLINE
| ID: mdl-22234187
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.
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Base de dados:
MEDLINE
Assunto principal:
Saccharomyces cerevisiae
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Mutagênese
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Desoxirribonucleosídeos
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Replicação do DNA
Idioma:
En
Ano de publicação:
2012
Tipo de documento:
Article