Cargando…
Reduced sister chromatid cohesion acts as a tumor penetrance modifier
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 zebrafis...
Autores principales: | , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2022
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9436123/ https://www.ncbi.nlm.nih.gov/pubmed/35994499 http://dx.doi.org/10.1371/journal.pgen.1010341 |
_version_ | 1784781292499369984 |
---|---|
author | 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. |
author_facet | 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. |
author_sort | Wang, Jun |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-9436123 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-94361232022-09-02 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. PLoS Genet Research Article 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. Public Library of Science 2022-08-22 /pmc/articles/PMC9436123/ /pubmed/35994499 http://dx.doi.org/10.1371/journal.pgen.1010341 Text en © 2022 Wang et al https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Article 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. Reduced sister chromatid cohesion acts as a tumor penetrance modifier |
title | Reduced sister chromatid cohesion acts as a tumor penetrance modifier |
title_full | Reduced sister chromatid cohesion acts as a tumor penetrance modifier |
title_fullStr | Reduced sister chromatid cohesion acts as a tumor penetrance modifier |
title_full_unstemmed | Reduced sister chromatid cohesion acts as a tumor penetrance modifier |
title_short | Reduced sister chromatid cohesion acts as a tumor penetrance modifier |
title_sort | reduced sister chromatid cohesion acts as a tumor penetrance modifier |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9436123/ https://www.ncbi.nlm.nih.gov/pubmed/35994499 http://dx.doi.org/10.1371/journal.pgen.1010341 |
work_keys_str_mv | AT wangjun reducedsisterchromatidcohesionactsasatumorpenetrancemodifier AT thomashollyr reducedsisterchromatidcohesionactsasatumorpenetrancemodifier AT chenyu reducedsisterchromatidcohesionactsasatumorpenetrancemodifier AT percivalstefaniem reducedsisterchromatidcohesionactsasatumorpenetrancemodifier AT waldrepstephaniec reducedsisterchromatidcohesionactsasatumorpenetrancemodifier AT ramakerrynec reducedsisterchromatidcohesionactsasatumorpenetrancemodifier AT thompsonrobertg reducedsisterchromatidcohesionactsasatumorpenetrancemodifier AT coopersaraj reducedsisterchromatidcohesionactsasatumorpenetrancemodifier AT chongzechen reducedsisterchromatidcohesionactsasatumorpenetrancemodifier AT parantjohnm reducedsisterchromatidcohesionactsasatumorpenetrancemodifier |