page_title: Spindle checkpoint
section_title: Function of cohesion and its dissolution
hierarchical_section_title: Spindle checkpoint / Background on sister chromatid duplication, cohesion, and segregation / Mitosis: anchoring of chromosomes to the spindle and chromosome segregation / Sister chromatid cohesion during mitosis / Function of cohesion and its dissolution
caption_attribution_description: English: Scheme showing molecules implicated in sister chromosome cohesion. Realized in PowerPoint.
context_page_description: The spindle checkpoint, also known as the metaphase-to-anaphase transition, the spindle assembly checkpoint, or the mitotic checkpoint, is a cell cycle checkpoint during mitosis or meiosis that prevents the separation of the duplicated chromosomes until each chromosome is properly attached to the spindle. To achieve proper segregation, the two kinetochores on the sister chromatids must be attached to opposite spindle poles. Only this pattern of attachment will ensure that each daughter cell receives one copy of the chromosome. The defining biochemical feature of this checkpoint is the stimulation of the anaphase-promoting complex by M-phase cyclin-CDK complexes, which in turn causes the proteolytic destruction of cyclins and proteins that hold the sister chromatids together.
context_section_description: Centromeric cohesion resists the forces exerted by spindle microtubules towards the poles, which generate tension between sister kinetochores. In turn, this tension stabilizes the attachment microtubule-kinetochore, through a mechanism implicating the protein Aurora B (a review about this issue : Hauf and Watanabe 2004).
  Indeed, a decrease in the cellular levels of cohesin generates the premature separation of sister chromatids, as well as defects in chromosome congression at the metaphase plate and delocalization of the proteins in the chromosomal passenger complex, which contains the protein Aurora B.
  The proposed structure for the cohesin complex suggests that this complex connects directly both sister chromatids. In this proposed structure, the SMC components of cohesin play a structural role, so that the SMC heterodimer may function as a DNA binding protein, whose conformation is regulated by ATP. Scc1p and Scc3p, however, would play a regulatory role.
  In S. cerevisiae, Pds1p (also known as securin) regulates sister chromatids cohesion, because it binds and inhibits the protease Esp1p (separin or separase). When anaphase onset is triggered, the anaphase-promoting complex (APC/C or Cyclosome) degrades securin. APC/C is a ring E3 ubiquitin ligase that recruits an E2 ubiquitin-conjugating enzyme loaded with ubiquitin. Securin is recognized only if Cdc20, the activator subunit, is bound to the APC/C core.  When securin, Cdc20, and E2 are all bound to APC/C E2 ubiquitinates securin and selectively degrades it. Securin degradation releases the protease Esp1p/separase, which degrades the cohesin rings that link the two sister chromatids, therefore promoting sister chromatids separation. It has been also shown that Polo/Cdc5 kinase phosphorylates serine residues next to the cutting site for Scc1, and this phosphorylation would facilitate the cutting activity.
  Although this machinery is conserved through evolution, in vertebrates most cohesin molecules are released in prophase, independently of the presence of the APC/C, in a process dependent on Polo-like 1 (PLK1) and Aurora B. Yet it has been shown that a small quantity of Scc1 remains associated to centromeres in human cells until metaphase, and a similar amount is cut in anaphase, when it disappears from centromeres. On the other hand, some experiments show that sister chromatids cohesion in the arms is lost gradually after sister centromeres have separated, and sister chromatids move toward the opposite poles of the cell.
  According to some observations, a fraction of cohesins in the chromosomal arms and the centromeric cohesins are protected by the protein Shugoshin (Sgo1), avoiding their release during prophase. To be able to function as protector for the centromeric cohesion, Sgo1 must be inactivated at the beginning of anaphase, as well as Pds1p. In fact, both Pds1p and Sgo1 are substrates of APC/C in vertebrates.
caption: Scheme showing sister chromatids cohesion, anchored to spindle microtubules via their kinetochores
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