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Genome instability footprint under rapamycin and hydroxyurea treatments.
Li, Jing; Stenberg, Simon; Yue, Jia-Xing; Mikhalev, Ekaterina; Thompson, Dawn; Warringer, Jonas; Liti, Gianni.
Afiliación
  • Li J; State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, P. R. China.
  • Stenberg S; Université Côte d'Azur, CNRS, INSERM, IRCAN, Nice, France.
  • Yue JX; Department of Chemistry and Molecular Biology, University of Gothenburg, Gothenburg, Sweden.
  • Mikhalev E; State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, P. R. China.
  • Thompson D; Université Côte d'Azur, CNRS, INSERM, IRCAN, Nice, France.
  • Warringer J; Ginkgo Bioworks, Boston, Massachusetts, United States of America.
  • Liti G; Ginkgo Bioworks, Boston, Massachusetts, United States of America.
PLoS Genet ; 19(11): e1011012, 2023 Nov.
Article en En | MEDLINE | ID: mdl-37931001
The mutational processes dictating the accumulation of mutations in genomes are shaped by genetic background, environment and their interactions. Accurate quantification of mutation rates and spectra under drugs has important implications in disease treatment. Here, we used whole-genome sequencing and time-resolved growth phenotyping of yeast mutation accumulation lines to give a detailed view of the mutagenic effects of rapamycin and hydroxyurea on the genome and cell growth. Mutation rates depended on the genetic backgrounds but were only marginally affected by rapamycin. As a remarkable exception, rapamycin treatment was associated with frequent chromosome XII amplifications, which compensated for rapamycin induced rDNA repeat contraction on this chromosome and served to maintain rDNA content homeostasis and fitness. In hydroxyurea, a wide range of mutation rates were elevated regardless of the genetic backgrounds, with a particularly high occurrence of aneuploidy that associated with dramatic fitness loss. Hydroxyurea also induced a high T-to-G and low C-to-A transversion rate that reversed the common G/C-to-A/T bias in yeast and gave rise to a broad range of structural variants, including mtDNA deletions. The hydroxyurea mutation footprint was consistent with the activation of error-prone DNA polymerase activities and non-homologues end joining repair pathways. Taken together, our study provides an in-depth view of mutation rates and signatures in rapamycin and hydroxyurea and their impact on cell fitness, which brings insights for assessing their chronic effects on genome integrity.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Saccharomyces cerevisiae / Hidroxiurea Límite: Humans Idioma: En Revista: PLoS Genet Asunto de la revista: GENETICA Año: 2023 Tipo del documento: Article Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Saccharomyces cerevisiae / Hidroxiurea Límite: Humans Idioma: En Revista: PLoS Genet Asunto de la revista: GENETICA Año: 2023 Tipo del documento: Article Pais de publicación: Estados Unidos