View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector Dispatch R883 an mTORC1 substrate that negatively regulates inhibitors. Oncogene http://dx.doi.org/10.1038/ 1Department of Cancer and Cell Biology, insulin signaling. Science 332, 1322–1326. onc.2013.92. University of Cincinnati College of Medicine, 16. Chung, J., Kuo, C.J., Crabtree, G.R., and 19. She, Q.B., Halilovic, E., Ye, Q., Zhen, W., Cincinnati, OH 45267, USA. 2Institute for Blenis, J. (1992). Rapamycin-FKBP specifically Shirasawa, S., Sasazuki, T., Solit, D.B., and blocks growth-dependent activation of and Rosen, N. (2010). 4E-BP1 is a key effector of the Research in Immunology and Cancer (IRIC), signaling by the 70 kd S6 protein kinases. Cell oncogenic activation of the AKT and ERK Universite´ de Montre´ al, Montreal, 69, 1227–1236. signaling pathways that integrates their Quebec H3C 3J7, Canada. 3Department of 17. Zhang, Y., and Zheng, X.F. (2012). function in tumors. Cancer Cell 18, Pathology and Cell Biology, Faculty of mTOR-independent 4E-BP1 phosphorylation is 39–51. Medicine, Universite´ de Montre´ al, Montreal, associated with cancer resistance to mTOR 20. Shin, S., Wolgamott, L., Tcherkezian, J., kinase inhibitors. Cell Cycle 11, 594–603. Vallabhapurapu, S., Yu, Y., Roux, P.P., and Quebec, H3C 3J7, Canada. 18. Ducker, G.S., Atreya, C.E., Simko, J.P., Yoon, S.O. (2013). Glycogen synthase E-mail: [email protected], philippe. Hom, Y.K., Matli, M.R., Benes, C.H., Hann, B., kinase-3beta positively regulates protein [email protected] Nakakura, E.K., Bergsland, E.K., Donner, D.B., synthesis and cell proliferation through the et al. (2013). Incomplete inhibition of regulation of translation initiation factor phosphorylation of 4E-BP1 as a mechanism of 4E-binding protein 1. Oncogene http:// primary resistance to ATP-competitive mTOR dx.doi.org/10.1038/onc.2013.113. http://dx.doi.org/10.1016/j.cub.2013.08.030 Chromosome Segregation: Learning only when chromosomes are correctly bi-oriented and microtubules exert to Let Go tension across sister kinetochores [6]. How this relocation of Sgo1 is controlled, however, has been To ensure accurate chromosome segregation, cohesion between sister unknown. chromatids must be released in a controlled manner during mitosis. A new A number of ways to recruit Sgo1 study reveals how distinct centromere populations of the cohesin protector to centromeres have been reported, Sgo1 are regulated by microtubule attachments, cyclin-dependent kinases, but the relative contributions of these and the kinetochore kinase Bub1. pathways are debated. It is widely accepted that Sgo1 is brought to Jonathan M.G. Higgins and Sororin [3–5]. To fully separate centromeres when histone H2A is chromatids at anaphase, the remaining phosphorylated at Thr-120 Dividing cells must convey the correct cohesin is cleaved by the protease (H2AT120ph) by the kinetochore kinase complement of chromosomes to their Separase [2]. This raises the question Bub1 [9,10], though the structural basis offspring. Eukaryotes accomplish this of how cleavage of centromeric for this recruitment is unknown. Sgo1 by maintaining cohesion between cohesin is limited to anaphase. A can also bind to the heterochromatin replicated sister chromatids until simple possibility is that Separase only protein HP1, which itself binds chromosomes are bi-oriented on the becomes active at anaphase, and that chromatin by recognizing histone H3 mitotic spindle. Only once this has Sgo1 does not protect cohesin from trimethylated on Lys-9 (H3K9me3) [11]. been accomplished are the cleavage in mitosis. However, it has Although most HP1 is removed from attachments between chromatids been reported that Sgo1, when chromosomes during mitosis, a released, allowing them to be sorted inappropriately maintained at inner small population remains at inner accurately to opposite poles of the centromeres, prevents centromeres that could recruit Sgo1. dividing cell. Clearly then, although Separase-mediated cohesin cleavage However, other studies have found that sister chromatids may be inseparable [6]. Also, at least in budding yeast, key H3K9 methyltransferases are not at first, they must learn to let go when Sgo1–PP2A complexes may inhibit required for HP1 or Sgo1 localization in the time comes. A report from Liu, Jia Separase more directly [7]. Therefore, mitosis [12,13], and that HP1 binds to and Yu in this issue of Current Biology it is important to understand how the mitotic centromeres via the [1] provides new insight into this localization and activity of Sgo1 are chromosomal passenger complex process that may have broader regulated. (CPC) in a manner that excludes HP1 implications for our understanding of During prophase in mammalian cells, binding to Sgo1 [14]. An alternative inner centromere function. Sgo1 is found at inner centromeres potential contribution to inner Cohesion between sister chromatids (defined here as the area between the centromere Sgo1 localization is binding is maintained by cohesin complexes, chromatin regions that contain to cohesin itself, an interaction that together with regulators such as centromeric histone CENP-A; Figure 1). depends on phosphorylation of Sgo1 at Sororin [2]. In vertebrate mitosis, As chromosomes become bi-oriented, Thr-346 by cyclin-dependent kinases cohesin is removed from Sgo1 appears to move outwards, (Cdk) [5]. How do these proposed chromosomes in two steps. In relocating to two regions roughly mechanisms act together to control prophase, a mechanism involving coinciding with CENP-A-containing Sgo1 function? phosphorylation of cohesin and Sororin chromatin underlying kinetochores Although the dependency of Sgo1 by mitotic kinases removes the bulk of [1,6,8]. This movement of Sgo1 away localization on Bub1 activity is largely cohesin from chromosome arms from cohesin complexes located at unquestioned, the reason that (Figure 1). Cohesin at centromeres, inner centromeres might render centromeric cohesion depends on however, is protected by Sgo1–PP2A cohesin susceptible to cleavage by Bub1 is less clear [15,16]. Bub1 is a phosphatase complexes that Separase, and would provide a way to mitotic checkpoint protein, and counteract phosphorylation of cohesin make removal of cohesin favorable lowering Bub1 levels might lead to Current Biology Vol 23 No 19 R884 Prophase Prometaphase Metaphase Early anaphase to bind and protect cohesin at inner centromeres. Bi-orientation of chromosomes in metaphase leads to dephosphorylation of Thr-346, loss of P Release of P Sgo1 arm cohesin Sgo1 Bi-orientation Separase cohesin binding, and redistribution of P P Sgo1 toward H2AT120ph at inner Sgo1 Sgo1 Sgo1 Sgo1 Sgo1 Sgo1 kinetochores, where it cannot prevent cleavage of inner centromeric cohesin by Separase (Figure 1). Thus, microtubule attachment imposes Inner centromere an orchestrated change in the Kinetochore H2AT120ph Cohesin phosphorylation and binding partners Microtubules CENP-A-containing centromeric chromatin of Sgo1 to bring about its relocalization and to regulate cohesion. Current Biology The findings raise a number of questions. The model provides a Figure 1. Model for regulation of Sgo1 localization during mitosis. mechanism for Sgo1 regulation by During prophase, Sgo1 (green) is phosphorylated at Thr-346 and binds to cohesin complexes tension across bi-oriented (red) at the inner centromere between sister chromatids (pale blue). This inner centromeric chromosomes, but is it really tension accumulation of Sgo1 requires Bub1 and binding to H2AT120ph in an as yet undetermined that triggers Sgo1 relocation, or is manner (curved arrows). Cohesin on chromosome arms is released through the action of mitotic stable microtubule attachment to kinases, but Sgo1 protects inner centromere cohesin. Once the chromosomes become kinetochores sufficient? What makes bi-oriented, Sgo1 is dephosphosphorylated at Thr-346 and Sgo1 no longer binds to cohesin. Cdk-dependent phosphorylation of Instead, Sgo1 redistributes towards H2AT120ph (dark blue), in regions approximately coinciding with centromeric chromatin containing CENP-A (yellow). Once the mitotic Sgo1 responsive to attachment status checkpoint is satisfied, Separase is activated and cleaves the now unprotected cohesin at inner and could kinetochore-bound cyclin B centromeres. In anaphase, H2AT120ph begins to decline, and Sgo1 is eventually released. [6,17] play a role? Do these studies imply that HP1 has no role in Sgo1 recruitment? Not necessarily. One cohesion loss because the checkpoint H2AT120ph but was unable to bind possibility is that HP1 is important for is compromised and anaphase is cohesin was found at kinetochores, but Sgo1 localization prior to, but not initiated, rather than because Bub1 and was unable to localize to inner during, mitosis [13,14]. Alternatively, H2AT120ph are required for Sgo1 centromeres. Therefore, H2AT120ph ongoing work suggests that Sgo1 can localization [15]. In their new study, Liu binding appears important for all be retained at inner centromeres in et al. acknowledge that inactivation of centromeric enrichment of Sgo1, while mitosis by HP1, but that this system is Bub1 causes a weaker cohesion cohesin binding is important compromised in a wide range of cancer phenotype than loss of Sgo1 but argue specifically for the accumulation of cells (Y. Tanno and Y. Watanabe, that centromeric cohesion is flawed Sgo1 at inner centromeres. Notably, personal communication). The when Bub1 is depleted, even when Sgo1-T346A (which cannot bind