Reduced sister chromatid cohesion acts as a tumor penetrance modifier
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Published:2022-08-22
Issue:8
Volume:18
Page:e1010341
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ISSN:1553-7404
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Container-title:PLOS Genetics
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language:en
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Short-container-title:PLoS Genet
Author:
Wang Jun,
Thomas Holly R.ORCID,
Chen YuORCID,
Percival Stefanie M.,
Waldrep Stephanie C.,
Ramaker Ryne C.ORCID,
Thompson Robert G.ORCID,
Cooper Sara J.ORCID,
Chong ZechenORCID,
Parant John M.ORCID
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.
Funder
National Institute of Health
National Institutes of Health
National Cancer Institute
American Cancer Society
Comprehensive Cancer Center, University of Alabama at Birmingham
National Institute of General Medical Sciences
University of Alabama at Birmingham
Publisher
Public Library of Science (PLoS)
Subject
Cancer Research,Genetics (clinical),Genetics,Molecular Biology,Ecology, Evolution, Behavior and Systematics
Cited by
1 articles.
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