Editing Spindle checkpoint (section)

===== Function of cohesion and its dissolution =====
[[File:Chromosome cohesion - en.png|thumb|500px|Scheme showing sister chromatids cohesion, anchored to spindle [[microtubule]]s via their kinetochores]]
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 kinase|Aurora B]] (a review about this issue : Hauf and Watanabe 2004<ref name="Hauf2004">{{cite journal | vauthors = Hauf S, Watanabe Y | title = Kinetochore orientation in mitosis and meiosis | journal = Cell | volume = 119 | issue = 3 | pages = 317–27 | date = October 2004 | pmid = 15507205 | doi = 10.1016/j.cell.2004.10.014 | doi-access = free }}</ref>).

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.<ref name="Sonoda2001">{{cite journal | vauthors = Sonoda E, Matsusaka T, Morrison C, Vagnarelli P, Hoshi O, Ushiki T, Nojima K, Fukagawa T, Waizenegger IC, Peters JM, Earnshaw WC, Takeda S | title = Scc1/Rad21/Mcd1 is required for sister chromatid cohesion and kinetochore function in vertebrate cells | journal = Developmental Cell | volume = 1 | issue = 6 | pages = 759–70 | date = December 2001 | pmid = 11740938 | doi = 10.1016/S1534-5807(01)00088-0 | doi-access = free }}</ref><ref name="Vass2003">{{cite journal | vauthors = Vass S, Cotterill S, Valdeolmillos AM, Barbero JL, Lin E, Warren WD, Heck MM | title = Depletion of Drad21/Scc1 in Drosophila cells leads to instability of the cohesin complex and disruption of mitotic progression | journal = Current Biology | volume = 13 | issue = 3 | pages = 208–18 | date = February 2003 | pmid = 12573216 | doi = 10.1016/S0960-9822(03)00047-2 | bibcode = 2003CBio...13..208V | url = https://www.pure.ed.ac.uk/ws/files/10691787/Depletion_of_Drad21_Scc1_in_Drosophila_cells_leads_to_instability_of_the_and_disruption_of_mitotic_cohesin_complex_progression.pdf | hdl = 20.500.11820/b75b5706-3f21-4cfe-85be-466268afc918 | s2cid = 16037196 | hdl-access = free }}</ref>
The proposed structure for the cohesin complex suggests that this complex connects directly both sister chromatids.<ref name="Haering2002">{{cite journal | vauthors = Haering CH, Löwe J, Hochwagen A, Nasmyth K | title = Molecular architecture of SMC proteins and the yeast cohesin complex | journal = Molecular Cell | volume = 9 | issue = 4 | pages = 773–88 | date = April 2002 | pmid = 11983169 | doi = 10.1016/S1097-2765(02)00515-4 | doi-access = free }}</ref> 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 [[adenosine triphosphate|ATP]].<ref name="Hirano1999">{{cite journal | vauthors = Hirano T | title = SMC-mediated chromosome mechanics: a conserved scheme from bacteria to vertebrates? | journal = Genes & Development | volume = 13 | issue = 1 | pages = 11–9 | date = January 1999 | pmid = 9887095 | doi = 10.1101/gad.13.1.11 | doi-access = free }}</ref> Scc1p and Scc3p, however, would play a regulatory role.<ref name="Hirano2000" />

In ''S. cerevisiae'', Pds1p (also known as [[securin]]) regulates sister chromatids cohesion, because it binds and inhibits the protease [[Esp1]]p ('''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.<ref name="Ciosk1998">{{cite journal | vauthors = Ciosk R, Zachariae W, Michaelis C, Shevchenko A, Mann M, Nasmyth K | title = An ESP1/PDS1 complex regulates loss of sister chromatid cohesion at the metaphase to anaphase transition in yeast | journal = Cell | volume = 93 | issue = 6 | pages = 1067–76 | date = June 1998 | pmid = 9635435 | doi = 10.1016/S0092-8674(00)81211-8 | doi-access = free }}</ref> 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.<ref name="Alexandru2001">{{cite journal | vauthors = Alexandru G, Uhlmann F, Mechtler K, Poupart MA, Nasmyth K | title = Phosphorylation of the cohesin subunit Scc1 by Polo/Cdc5 kinase regulates sister chromatid separation in yeast | journal = Cell | volume = 105 | issue = 4 | pages = 459–72 | date = May 2001 | pmid = 11371343 | doi = 10.1016/S0092-8674(01)00362-2 | doi-access = free }}</ref>

Although this machinery is conserved through evolution,<ref name="Leismann2001">{{cite journal | vauthors = Leismann O, Herzig A, Heidmann S, Lehner CF | title = Degradation of Drosophila PIM regulates sister chromatid separation during mitosis | journal = Genes & Development | volume = 14 | issue = 17 | pages = 2192–205 | date = September 2000 | pmid = 10970883 | pmc = 316890 | doi = 10.1101/gad.176700 }}</ref><ref name="Zur2001">{{cite journal | vauthors = Zur A, Brandeis M | title = Securin degradation is mediated by fzy and fzr, and is required for complete chromatid separation but not for cytokinesis | journal = The EMBO Journal | volume = 20 | issue = 4 | pages = 792–801 | date = February 2001 | pmid = 11179223 | pmc = 145417 | doi = 10.1093/emboj/20.4.792 }}</ref> 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.<ref name="Sumara2000">{{cite journal | vauthors = Sumara I, Vorlaufer E, Gieffers C, Peters BH, Peters JM | title = Characterization of vertebrate cohesin complexes and their regulation in prophase | journal = The Journal of Cell Biology | volume = 151 | issue = 4 | pages = 749–62 | date = November 2000 | pmid = 11076961 | pmc = 2169443 | doi = 10.1083/jcb.151.4.749 }}</ref> 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.<ref name="Losada2000">{{cite journal | vauthors = Losada A, Yokochi T, Kobayashi R, Hirano T | title = Identification and characterization of SA/Scc3p subunits in the Xenopus and human cohesin complexes | journal = The Journal of Cell Biology | volume = 150 | issue = 3 | pages = 405–16 | date = August 2000 | pmid = 10931856 | pmc = 2175199 | doi = 10.1083/jcb.150.3.405 }}</ref> 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.<ref name="Gimenez2004">{{cite journal | vauthors = Giménez-Abián JF, Sumara I, Hirota T, Hauf S, Gerlich D, de la Torre C, Ellenberg J, Peters JM | title = Regulation of sister chromatid cohesion between chromosome arms | journal = Current Biology | volume = 14 | issue = 13 | pages = 1187–93 | date = July 2004 | pmid = 15242616 | doi = 10.1016/j.cub.2004.06.052 | doi-access = free | bibcode = 2004CBio...14.1187G }}</ref><ref name="Paliulis2004">{{cite journal | vauthors = Paliulis LV, Nicklas RB | title = Micromanipulation of chromosomes reveals that cohesion release during cell division is gradual and does not require tension | journal = Current Biology | volume = 14 | issue = 23 | pages = 2124–9 | date = December 2004 | pmid = 15589155 | doi = 10.1016/j.cub.2004.11.052 | doi-access = free | bibcode = 2004CBio...14.2124P }}</ref>

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.<ref name="Nakajima2007">{{cite journal | vauthors = Nakajima M, Kumada K, Hatakeyama K, Noda T, Peters JM, Hirota T | title = The complete removal of cohesin from chromosome arms depends on separase | journal = Journal of Cell Science | volume = 120 | issue = Pt 23 | pages = 4188–96 | date = December 2007 | pmid = 18003702 | doi = 10.1242/jcs.011528 | doi-access = free }}</ref><ref name="McGuiness2005">{{cite journal | vauthors = McGuinness BE, Hirota T, Kudo NR, Peters JM, Nasmyth K | title = Shugoshin prevents dissociation of cohesin from centromeres during mitosis in vertebrate cells | journal = PLOS Biology | volume = 3 | issue = 3 | pages = e86 | date = March 2005 | pmid = 15737064 | pmc = 1054882 | doi = 10.1371/journal.pbio.0030086 | doi-access = free }} {{open access}}</ref> 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.<ref name="Salic2004">{{cite journal | vauthors = Salic A, Waters JC, Mitchison TJ | title = Vertebrate shugoshin links sister centromere cohesion and kinetochore microtubule stability in mitosis | journal = Cell | volume = 118 | issue = 5 | pages = 567–78 | date = September 2004 | pmid = 15339662 | doi = 10.1016/j.cell.2004.08.016 | doi-access = free }}</ref>