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Quickly switching of spindle checkpoint states is due to negative feedback at kinetochrores

 

During cell mitosis, spindle assemble checkpoint (SAC) is activated by kinetochores at mitotic entry to prevent separation of the duplicated chromosomes, and disappears when all chromosomes are attached. Kinetochores are able to rapidly switch SAC signaling between the ON and OFF states in response to the changes in microtubule occupancy, but the mechanism is obscure. Nijenhuis et al. found this phenomenon arises due to localized negative feedback of SAC signal, which ensure kinetochres switch SAC signalling OFF rapidly. The letter was published on Nature Cell Biology.

 

By using targeted screen with short interfering RNAs (siRNAs), researchers found the depletions of PP1 and PP2A-B56 delayed mitotic exit. PP1 is known as the silencer of SAC signal in Schizoaccharomyces pombe, Saccharomyces cerevisiae and Caenorhabditis elegans, also, PP2A-B56 has ability to induce SAC silencing, indicating PP1 and PP2A-B56 are key factors of the SAC negative feedback process. Further investigation revealed the regulatory steps: SAC signal recruits PP2A-B56 to kinetochroes, then antagonizes Aurora B to recruit PP1, after that, PP1 silences the SAC and removes PP2A-B56. These feedback steps let SAC rapidly switches to ON state without antagonizing phosphatase activity. The study provides in-depth look into mechanism of mitosis.

 

Reference:
Nat Cell Biol. 2014 Nov 17.10.1038/ncb3065.

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