Prolonged mitosis causes separase deregulation and chromosome nondisjunction
| Autor: | Norihisa Shindo, Makoto Otsuki, Kazuhiko S.K. Uchida, Toru Hirota |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Cohesin Mitosis Biology General Biochemistry Genetics and Molecular Biology Cell biology Chromosome segregation 03 medical and health sciences Mice 030104 developmental biology 0302 clinical medicine Nondisjunction Chromosome Segregation Sister chromatids Animals Humans Rabbits Separase Metaphase 030217 neurology & neurosurgery Anaphase |
| Zdroj: | Cell reports. 34(3) |
| ISSN: | 2211-1247 |
| Popis: | Intercellular karyotype diversity, or aneuploidy, is a widespread feature of cancers propagated through continuous mitotic chromosome segregation errors, the condition called chromosomal instability. The protease separase is an essential enzyme that sever cohesin between sister chromatids, and a probe for separase activity has articulated that separase undergoes abrupt activation shortly before anaphase onset, after being suppressed through metaphase; however the relevance of this robust control remains unclear. In this study, we found that separase activates precociously during prolonged metaphase, consistently in multiple types of cancer cell lines. An artificial extension of metaphase alone in chromosomally stable diploid cells was found to induce precocious activation. These kinetic changes resulted in an incomplete removal of cohesin and emergence of chromosomal bridges in anaphase. Conversely, in transformed cells, shortening back of their prolonged metaphase restored the robust activation of separase and ameliorated anaphase bridge formation. These observations suggest that retarded metaphase progression directly affects the separase activation profile, which provides a previously unanticipated etiology for chromosomal instability in cancers and underscores the significance of the swift mitotic transitions for fail-safe chromosome segregation. |
| Databáze: | OpenAIRE |
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