Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 119, Issue 40, Pages -Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.2204071119
Keywords
chromosome instability; chromatin; centromere; cancer-testis genes; condensin
Categories
Funding
- MOST National Key R&D Program of China [2018YFA0106903]
- Government of Guangdong province
- Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH
- Intramural Research Program of the National Institute of Allergy and Infectious Diseases, NIH
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Many tumors express meiotic genes that can cause chromosome instability. The abnormal expression of meiotic cohesins is associated with chromosome missegregation, DNA damage, and altered gene expression. Additionally, meiotic cohesins localize to the same sites as BORIS/CTCFL, rather than the CTCF sites associated with somatic cohesins.
Many tumors express meiotic genes that could potentially drive somatic chromosome instability. While germline cohesin subunits SMC1B, STAG3, and REC8 are widely expressed in many cancers, messenger RNA and protein for RAD21L subunit are expressed at very low levels. To elucidate the potential of meiotic cohesins to contribute to genome instability, their expression was investigated in human cell lines, predominately in DLD-1. While the induction of the REC8 complex resulted in a mild mitotic phenotype, the expression of the RAD21L complex produced an arrested but viable cell pool, thus providing a source of DNA damage, mitotic chromosome missegregation, sporadic polyteny, and altered gene expression. We also found that genomic binding profiles of ectopically expressed meiotic cohesin complexes were reminiscent of their corresponding specific binding patterns in testis. Furthermore, meiotic cohesins were found to localize to the same sites as BORIS/CTCFL, rather than CTCF sites normally associated with the somatic cohesin complex. These findings highlight the existence of a germline epigenomic memory that is conserved in cells that normally do not express meiotic genes. Our results reveal a mechanism of action by unduly expressed meiotic cohesins that potentially links them to aneuploidy and chromosomal mutations in affected cells.
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