Shugoshin prevents dissociation of cohesin from centromeres during mitosis in vertebrate cells.
Cohesion between sister chromatids is essential for their bi-orientation on mitotic spindles. It is mediated by a multisubunit complex called cohesin. In yeast, proteolytic cleavage of cohesin's alpha kleisin subunit at the onset of anaphase removes cohesin from both centromeres and chromosome arms and thus triggers sister chromatid separation. In animal cells, most cohesin is removed from chromosome arms during prophase via a separase-independent pathway involving phosphorylation of its Scc3-SA1/2 subunits. Cohesin at centromeres is refractory to this process and persists until metaphase, whereupon its alpha kleisin subunit is cleaved by separase, which is thought to trigger anaphase. What protects centromeric cohesin from the prophase pathway? Potential candidates are proteins, known as shugoshins, that are homologous to Drosophila MEI-S332 and yeast Sgo1 proteins, which prevent removal of meiotic cohesin complexes from centromeres at the first meiotic division. A vertebrate shugoshin-like protein associates with centromeres during prophase and disappears at the onset of anaphase. Its depletion by RNA interference causes HeLa cells to arrest in mitosis. Most chromosomes bi-orient on a metaphase plate, but precocious loss of centromeric cohesin from chromosomes is accompanied by loss of all sister chromatid cohesion, the departure of individual chromatids from the metaphase plate, and a permanent cell cycle arrest, presumably due to activation of the spindle checkpoint. Remarkably, expression of a version of Scc3-SA2 whose mitotic phosphorylation sites have been mutated to alanine alleviates the precocious loss of sister chromatid cohesion and the mitotic arrest of cells lacking shugoshin. These data suggest that shugoshin prevents phosphorylation of cohesin's Scc3-SA2 subunit at centromeres during mitosis. This ensures that cohesin persists at centromeres until activation of separase causes cleavage of its alpha kleisin subunit. Centromeric cohesion is one of the hallmarks of mitotic chromosomes. Our results imply that it is not an intrinsically stable property, because it can easily be destroyed by mitotic kinases, which are kept in check by shugoshin.
McGuinness
Barry E
BE
Research Institute of Molecular Pathology, Vienna, Austria.
Hirota
Toru
T
Kudo
Nobuaki R
NR
Peters
Jan-Michael
JM
Nasmyth
Kim
K
D000595:Amino Acid Sequence; D000705:Anaphase / Q000502:physiology; D000818:Animals; D001483:Base Sequence; D018797:Cell Cycle Proteins / Q000502:physiology*; D002503:Centromere / Q000502:physiology*; D002868:Chromosomal Proteins, Non-Histone; D017931:DNA Primers; D005656:Fungal Proteins / Q000502:physiology*; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008938:Mitosis / Q000502:physiology*; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000502:physiology*; D010446:Peptide Fragments / Q000737:chemistry; D011506:Proteins / Q000737:chemistry / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D012854:Sister Chromatid Exchange; D000097722:Cohesins
D018797:Cell Cycle Proteins; D002868:Chromosomal Proteins, Non-Histone; D017931:DNA Primers; D005656:Fungal Proteins; D009687:Nuclear Proteins; D010446:Peptide Fragments; D011506:Proteins; D034741:RNA, Small Interfering; D000097722:Cohesins; C496644:SGO1 protein, human
Genes Dev. 1998 Jul 1;12(13):1986-97
9649503
J Cell Biol. 1998 Sep 21;142(6):1595-604
9744887
Nature. 1999 Jul 1;400(6739):37-42
10403247
Science. 1999 Jul 16;285(5426):418-22
10411507
J Cell Biol. 2003 Apr 28;161(2):281-94
12707311
J Cell Biol. 2003 Apr 28;161(2):267-80
12719470
Science. 2003 May 16;300(5622):1152-5
12750522
Nat Rev Mol Cell Biol. 2003 Nov;4(11):842-54
14625535
Dev Cell. 2003 Dec;5(6):853-64
14667408
Nature. 2004 Feb 5;427(6974):510-7
14730319
Curr Biol. 2004 Feb 17;14(4):287-301
14972679
Science. 2004 Feb 27;303(5662):1367-70
14752166
Curr Biol. 2004 Apr 6;14(7):560-72
15062096
Curr Biol. 2004 Jul 13;14(13):1187-93
15242616
Cell. 2004 Sep 3;118(5):567-78
15339662
Mol Cell. 2004 Sep 24;15(6):951-64
15383284
Nat Genet. 2004 Nov;36(11):1174-80
15475954
J Cell Biol. 1994 Sep;126(5):1241-53
8063861
Cell. 1995 Oct 20;83(2):247-56
7585942
Nature. 1996 May 30;381(6581):438-41
8632802
Genes Dev. 1996 Dec 15;10(24):3081-93
8985178
Chromosome Res. 1997 Feb;5(1):66-8
9088645
J Cell Biol. 1998 Mar 9;140(5):1003-12
9490715
Curr Biol. 1998 Mar 26;8(7):377-85
9545195
Cell. 1998 Jun 12;93(6):1067-76
9635435
PLoS Biol. 2005 Mar;3(3):e69
15737063
Cell. 2000 Jun 23;101(7):789-800
10892749
Nat Cell Biol. 2000 Aug;2(8):492-9
10934469
J Cell Biol. 2000 Nov 13;151(4):749-62
11076961
Cell. 2000 Oct 27;103(3):375-86
11081625
Cell. 2000 Oct 27;103(3):387-98
11081626
Cell. 2000 Oct 27;103(3):399-410
11081627
Nat Rev Genet. 2001 Apr;2(4):280-91
11283700
Cell. 2001 May 18;105(4):459-72
11371343
Genes Dev. 2001 Dec 1;15(23):3118-29
11731476
Dev Cell. 2001 Dec;1(6):759-70
11740938
Cell. 2001 Dec 14;107(6):715-26
11747808
Mol Cell. 2002 Mar;9(3):515-25
11931760
Mol Cell. 2002 Apr;9(4):773-88
11983169
Genes Dev. 2002 Dec 1;16(23):3004-16
12464631
EMBO J. 2003 Feb 17;22(4):797-806
12574116
Cell. 2003 Feb 21;112(4):407-21
12600307