부산대학교 도서관

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. Author summary: Tumorigenesis often involves the inactivation of tumor suppressor genes. This often encompasses an inactivation mutation in one allele and loss of the other wild-type allele, referred to as loss of heterozygosity (LOH). The rate at which the cells lose the wild-type allele can influence the timing of tumor onset, and therefore an indicator of a patient's risk of cancer. Factors that influence this process could be used as a predictive indicator of cancer risk, however these factors are still unclear. We demonstrate that partial impairment of sister chromatid cohesion (SCC), a fundamental component of the chromosome segregation in mitosis and homologous recombination repair, enhanced tumorigenesis. Our data suggest this is through elevated levels of mitotic recombination derived p53 LOH. This study emphasizes the importance of understanding how impaired SCC, mitotic recombination rates, and LOH rates influence cancer risk. [ABSTRACT FROM AUTHOR]