Global analysis of genomic instability caused by DNA replication stress in Saccharomyces cerevisiae.
Proc Natl Acad Sci U S A
; 113(50): E8114-E8121, 2016 12 13.
Article
em En
| MEDLINE
| ID: mdl-27911848
ABSTRACT
DNA replication stress (DRS)-induced genomic instability is an important factor driving cancer development. To understand the mechanisms of DRS-associated genomic instability, we measured the rates of genomic alterations throughout the genome in a yeast strain with lowered expression of the replicative DNA polymerase δ. By a genetic test, we showed that most recombinogenic DNA lesions were introduced during S or G2 phase, presumably as a consequence of broken replication forks. We observed a high rate of chromosome loss, likely reflecting a reduced capacity of the low-polymerase strains to repair double-stranded DNA breaks (DSBs). We also observed a high frequency of deletion events within tandemly repeated genes such as the ribosomal RNA genes. By whole-genome sequencing, we found that low levels of DNA polymerase δ elevated mutation rates, both single-base mutations and small insertions/deletions. Finally, we showed that cells with low levels of DNA polymerase δ tended to accumulate small promoter mutations that increased the expression of this polymerase. These deletions conferred a selective growth advantage to cells, demonstrating that DRS can be one factor driving phenotypic evolution.
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MEDLINE
Assunto principal:
Saccharomyces cerevisiae
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DNA Fúngico
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Instabilidade Genômica
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Replicação do DNA
Idioma:
En
Ano de publicação:
2016
Tipo de documento:
Article