PUBLICATION

Reduced sister chromatid cohesion acts as a tumor penetrance modifier

Authors
Wang, J., Thomas, H.R., Chen, Y., Percival, S.M., Waldrep, S.C., Ramaker, R.C., Thompson, R.G., Cooper, S.J., Chong, Z., Parant, J.M.
ID
ZDB-PUB-220824-23
Date
2022
Source
PLoS Genetics   18: e1010341 (Journal)
Registered Authors
Parant, John, Percival, Stefanie M., Thomas, Holly R.
Keywords
none
MeSH Terms
  • Acetyltransferases/genetics
  • Animals
  • Cell Cycle Proteins/genetics
  • Cell Cycle Proteins/metabolism
  • Chromatids/genetics
  • Chromatids/metabolism
  • Chromosomal Proteins, Non-Histone/genetics
  • Chromosomal Proteins, Non-Histone/metabolism
  • Chromosome Segregation*/genetics
  • Humans
  • Mice
  • Neoplasms*/genetics
  • Penetrance
  • Tumor Suppressor Protein p53/genetics
  • Zebrafish/genetics
PubMed
35994499 Full text @ PLoS Genet.
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.
Genes / Markers
Figures
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Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping