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Reduced sister chromatid cohesion acts as a tumor penetrance modifier.
Wang, Jun; Thomas, Holly R; Chen, Yu; Percival, Stefanie M; Waldrep, Stephanie C; Ramaker, Ryne C; Thompson, Robert G; Cooper, Sara J; Chong, Zechen; Parant, John M.
Afiliación
  • Wang J; Department of Pharmacology and Toxicology, University of Alabama at Birmingham Heersink School of Medicine, Birmingham, Alabama, United States of America.
  • Thomas HR; Department of Pharmacology and Toxicology, University of Alabama at Birmingham Heersink School of Medicine, Birmingham, Alabama, United States of America.
  • Chen Y; Department of Genetics, University of Alabama at Birmingham Heersink School of Medicine, Birmingham, Alabama, United States of America.
  • Percival SM; Informatics Institute, University of Alabama at Birmingham Heersink School of Medicine, Alabama, United States of America.
  • Waldrep SC; Department of Pharmacology and Toxicology, University of Alabama at Birmingham Heersink School of Medicine, Birmingham, Alabama, United States of America.
  • Ramaker RC; Department of Pharmacology and Toxicology, University of Alabama at Birmingham Heersink School of Medicine, Birmingham, Alabama, United States of America.
  • Thompson RG; Hudson Alpha Institute for Biotechnology, Huntsville, Alabama, United States of America.
  • Cooper SJ; Department of Pharmacology and Toxicology, University of Alabama at Birmingham Heersink School of Medicine, Birmingham, Alabama, United States of America.
  • Chong Z; Hudson Alpha Institute for Biotechnology, Huntsville, Alabama, United States of America.
  • Parant JM; Department of Genetics, University of Alabama at Birmingham Heersink School of Medicine, Birmingham, Alabama, United States of America.
PLoS Genet ; 18(8): e1010341, 2022 08.
Article en En | MEDLINE | ID: mdl-35994499
ABSTRACT
Sister chromatid cohesion (SCC) is an important process in chromosome segregation. ESCO2 is essential for establishment of SCC and is often deleted/altered in human cancers. We demonstrate that esco2 haploinsufficiency results in reduced SCC and accelerates the timing of tumor onset in both zebrafish and mouse p53 heterozygous null models, but not in p53 homozygous mutant or wild-type animals. These data indicate that esco2 haploinsufficiency accelerates tumor onset in a loss of heterozygosity (LOH) sensitive background. Analysis of The Cancer Genome Atlas (TCGA) confirmed ESCO2 deficient tumors have elevated number of LOH events throughout the genome. Further, we demonstrated heterozygous loss of sgo1, important in maintaining SCC, also results in reduced SCC and accelerated tumor formation in a p53 heterozygous background. Surprisingly, while we did observe elevated levels of chromosome missegregation and micronuclei formation in esco2 heterozygous mutant animals, this chromosomal instability did not contribute to the accelerated tumor onset in a p53 heterozygous background. Interestingly, SCC also plays a role in homologous recombination, and we did observe elevated levels of mitotic recombination derived p53 LOH in tumors from esco2 haploinsufficient animals; as well as elevated levels of mitotic recombination throughout the genome of human ESCO2 deficient tumors. Together these data suggest that reduced SCC contributes to accelerated tumor penetrance through elevated mitotic recombination.
Asunto(s)

Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Segregación Cromosómica / Neoplasias Límite: Animals / Humans Idioma: En Revista: PLoS Genet Asunto de la revista: GENETICA Año: 2022 Tipo del documento: Article País de afiliación: Estados Unidos

Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Segregación Cromosómica / Neoplasias Límite: Animals / Humans Idioma: En Revista: PLoS Genet Asunto de la revista: GENETICA Año: 2022 Tipo del documento: Article País de afiliación: Estados Unidos