Centromeric cohesin is protected from cleavage by the recruitment of Protein phosphatase 2A by Shugoshin.
In mitosis and meiosis, sister chromatids are bound together by the ring shaped cohesin complex. The centromeres of chromosomes assemble kinetochore complexes that mediate interaction with spindle microtubules. While cohesins detach from chromosome arms early in mitosis, cohesin around the centromere is dissolved much later, in anaphase, through cohesin cleavage by the protease separase. The persistence of centromeric cohesin requires a family of kinetochore localized proteins called the shugoshins. Two studies by Riedel et al. and Kitajima et al. in Nature now show that shugoshin (Sgo) recruits a subtype of protein phosphatase 2A (PP2A) to the centrosome, protecting cohesin from degradation. A further study by Brar et al. investigates whether phosphorylation of the meiosis specific cohesin subunit regulates the loss of centromeric cohesins.
Riedel et al. and Kitajima et al. both show that PP2A co-purifies with Sgo during meiosis in S. cerevisiae, S. pombe and human HeLa cells. PP2A is a hetero-trimeric complex, comprising A (scaffold), B (regulatory) and C (catalytic) subunits. Sgo interacts with PP2A that contains B’ type regulatory subunits. Indeed, B’ subunits are predominantly localized to the centrosome with Sgo proteins, while other PP2A subunits are localized throughout the cell. Reduction of PP2A protein levels in either yeast or HeLa cells increases the frequency of random chromatid segregation. Kitajima et al. show that the human cohesin subunit SA2 is dephosphorylated when chromatin-bound, while free SA2 remains phosphorylated. Furthermore, purified human Sgo can counteract the phosphorylation of SA2. Both groups reveal how tethering of PP2A to chromosomes prevents the removal of cohesins and leads to their dephosphorylation.Taken together, these results suggest that the main function of shugoshin is to recruit PP2A to the centrosome, where it dephosphorylates cohesin allowing for timely chromatid segregation.
A study by Brar et al. published online in Nature examines whether phosphorylation of cohesin contributes to cohesin loss at the centrosome during meiosis, following on from data showing that the Polo-like kinase Cdc5 is required for cleavage of the cohesin subunit Rec8 and consequently chromosome segregation. The authors define the putative sites of cohesin phosphorylation and mutate them. Only mutation of multiple sites delayed prophase of meiosis I. Surprisingly, Brar et al. show that deletion Spo11, a gene required for the creation of double stranded breaks and therefore meiotic recombination, abolishes the requirement for cohesin phosphorylation. Thus, Rec8 phosphorylation is important largely for the first meiotic division, while recombination in the second meiotic division is essential for silencing of spindle checkpoints and the timely removal of cohesins.
These studies reveal how Sgo recruits PP2A to the centrosome, so as to reduce the phosphorylation, cleavage and removal of cohesin. Cohesin phosphorylation is less important for its removal in the second meiotic cleavage where recombination occurs.
Clare Garvey Signaling Gateway
References
Tomoya S Kitajima, Takeshi Sakuno, Kei-ichiro Ishiguro, Shun-ichiro Iemura, Tohru Natsume, Shigehiro A Kawashima & Yoshinori Watanabe. Shugoshin collaborates with protein phosphatase 2A to protect cohesin. Nature441, 46-52 (2006) | Article | PubMed |
Christian G Riedel, Vittorio L Katis, Yuki Katou Yuki Katou, Saori Mori, Takehiko Itoh, Wolfgang Helmhart, Marta Gálová, Mark Petronczki, Juraj Gregan, Bulent Cetin, Ingrid Mudrak, Egon Ogris, Karl Mechtler, Laurence Pelletier, Frank Buchholz, Katsuhiko Shirahige & Kim Nasmyth. Protein phosphatase 2A protects centromeric sister chromatid cohesion during meiosis I. Nature441, 53-56 (2006) | Article | PubMed |
Paul Megee. Molecular biology: Chromosome guardians on duty. Nature441, 35-37 (2006) | Article | PubMed |
Gloria A. Brar, Brendan M. Kiburz, Yi Zhang, Ji-Eun Kim, Forest White and Angelika Amon. Rec8 phosphorylation and recombination promote the step-wise loss of cohesins in meiosis. Nature441, 532-536 (25 May 2006) | Article | PubMed |
