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Trajectory and uniqueness of mutational signatures in yeast mutators.
Loeillet, Sophie; Herzog, Mareike; Puddu, Fabio; Legoix, Patricia; Baulande, Sylvain; Jackson, Stephen P; Nicolas, Alain G.
Afiliação
  • Loeillet S; Institut Curie, Paris Sciences et Lettres Research University, CNRS, UMR3244, 75248 Paris Cedex 05, France.
  • Herzog M; Sorbonne Universités, Université Pierre et Marie Curie Paris 06, CNRS, UMR3244, 75248 Paris Cedex 05, France.
  • Puddu F; Wellcome/Cancer Research UK Gurdon Institute and Department of Biochemistry, Cambridge CB2 1QN, United Kingdom.
  • Legoix P; Wellcome/Cancer Research UK Gurdon Institute and Department of Biochemistry, Cambridge CB2 1QN, United Kingdom.
  • Baulande S; ICGex NGS Platform, Institut Curie, 75248 Paris Cedex 05, France.
  • Jackson SP; ICGex NGS Platform, Institut Curie, 75248 Paris Cedex 05, France.
  • Nicolas AG; Wellcome/Cancer Research UK Gurdon Institute and Department of Biochemistry, Cambridge CB2 1QN, United Kingdom.
Proc Natl Acad Sci U S A ; 117(40): 24947-24956, 2020 10 06.
Artigo em Inglês | MEDLINE | ID: mdl-32968016
ABSTRACT
The acquisition of mutations plays critical roles in adaptation, evolution, senescence, and tumorigenesis. Massive genome sequencing has allowed extraction of specific features of many mutational landscapes but it remains difficult to retrospectively determine the mechanistic origin(s), selective forces, and trajectories of transient or persistent mutations and genome rearrangements. Here, we conducted a prospective reciprocal approach to inactivate 13 single or multiple evolutionary conserved genes involved in distinct genome maintenance processes and characterize de novo mutations in 274 diploid Saccharomyces cerevisiae mutation accumulation lines. This approach revealed the diversity, complexity, and ultimate uniqueness of mutational landscapes, differently composed of base substitutions, small insertions/deletions (InDels), structural variants, and/or ploidy variations. Several landscapes parallel the repertoire of mutational signatures in human cancers while others are either novel or composites of subsignatures resulting from distinct DNA damage lesions. Notably, the increase of base substitutions in the homologous recombination-deficient Rad51 mutant, specifically dependent on the Polζ translesion polymerase, yields COSMIC signature 3 observed in BRCA1/BRCA2-mutant breast cancer tumors. Furthermore, "mutome" analyses in highly polymorphic diploids and single-cell bottleneck lineages revealed a diverse spectrum of loss-of-heterozygosity (LOH) signatures characterized by interstitial and terminal chromosomal events resulting from interhomolog mitotic cross-overs. Following the appearance of heterozygous mutations, the strong stimulation of LOHs in the rad27/FEN1 and tsa1/PRDX1 backgrounds leads to fixation of homozygous mutations or their loss along the lineage. Overall, these mutomes and their trajectories provide a mechanistic framework to understand the origin and dynamics of genome variations that accumulate during clonal evolution.
Assuntos
Texto completo: Disponível Coleções: Bases de dados internacionais Base de dados: MEDLINE Assunto principal: Saccharomyces cerevisiae / Neoplasias da Mama / Carcinogênese / Mutação Limite: Feminino / Humanos Idioma: Inglês Revista: Proc Natl Acad Sci U S A Ano de publicação: 2020 Tipo de documento: Artigo País de afiliação: França

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Texto completo: Disponível Coleções: Bases de dados internacionais Base de dados: MEDLINE Assunto principal: Saccharomyces cerevisiae / Neoplasias da Mama / Carcinogênese / Mutação Limite: Feminino / Humanos Idioma: Inglês Revista: Proc Natl Acad Sci U S A Ano de publicação: 2020 Tipo de documento: Artigo País de afiliação: França