title: Wapl is an essential regulator of chromatin structure and chromosome segregation.
abstract: Mammalian genomes contain several billion base pairs of DNA that are packaged in chromatin fibres. At selected gene loci, cohesin complexes have been proposed to arrange these fibres into higher-order structures, but how important this function is for determining overall chromosome architecture and how the process is regulated are not well understood. Using conditional mutagenesis in the mouse, here we show that depletion of the cohesin-associated protein Wapl stably locks cohesin on DNA, leads to clustering of cohesin in axial structures, and causes chromatin condensation in interphase chromosomes. These findings reveal that the stability of cohesin-DNA interactions is an important determinant of chromatin structure, and indicate that cohesin has an architectural role in interphase chromosome territories. Furthermore, we show that regulation of cohesin-DNA interactions by Wapl is important for embryonic development, expression of genes such as c-myc (also known as Myc), and cell cycle progression. In mitosis, Wapl-mediated release of cohesin from DNA is essential for proper chromosome segregation and protects cohesin from cleavage by the protease separase, thus enabling mitotic exit in the presence of functional cohesin complexes.
authors: Research Institute of Molecular Pathology, Dr. Bohr-Gasse 7, 1030 Vienna, Austria.
authors: Antonio
authors: A
authors: Tedeschi
authors: Gordana
authors: G
authors: Wutz
authors: Sébastien
authors: S
authors: Huet
authors: Markus
authors: M
authors: Jaritz
authors: Annelie
authors: A
authors: Wuensche
authors: Erika
authors: E
authors: Schirghuber
authors: Iain Finley
authors: IF
authors: Davidson
authors: Wen
authors: W
authors: Tang
authors: David A
authors: DA
authors: Cisneros
authors: Venugopal
authors: V
authors: Bhaskara
authors: Tomoko
authors: T
authors: Nishiyama
authors: Alipasha
authors: A
authors: Vaziri
authors: Anton
authors: A
authors: Wutz
authors: Jan
authors: J
authors: Ellenberg
authors: Jan-Michael
authors: JM
authors: Peters
mesh_terms: D000818:Animals; D002453:Cell Cycle / Q000235:genetics; D018797:Cell Cycle Proteins / Q000378:metabolism; D002842:Chromatids / Q000235:genetics / Q000378:metabolism; D002843:Chromatin / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D002868:Chromosomal Proteins, Non-Histone / Q000378:metabolism; D020090:Chromosome Segregation / Q000235:genetics; D033481:Chromosomes, Mammalian / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D004247:DNA / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D047108:Embryonic Development / Q000235:genetics; D010450:Endopeptidases / Q000378:metabolism; D005786:Gene Expression Regulation / Q000235:genetics; D016259:Genes, myc / Q000235:genetics; D007399:Interphase; D051379:Mice; D008938:Mitosis; D011418:Prophase; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D064247:Separase; D000097722:Cohesins
chemical_list: D018797:Cell Cycle Proteins; D002843:Chromatin; D002868:Chromosomal Proteins, Non-Histone; D004247:DNA; D004268:DNA-Binding Proteins; D010450:Endopeptidases; D011506:Proteins; D064247:Separase; D000097722:Cohesins; C496335:WAPL protein, mouse
references: Science. 2001 Aug 17;293(5533):1320-3
references: 11509732
references: Nature. 2010 Sep 23;467(7314):430-5
references: 20720539
references: Hum Genet. 1998 Feb;102(2):241-51
references: 9521598
references: Semin Cell Dev Biol. 2011 Oct;22(8):906-12
references: 21782962
references: Genesis. 2000 Feb;26(2):113-5
references: 10686601
references: Curr Biol. 2006 Dec 19;16(24):2406-17
references: 17112726
references: Cell. 2013 Jun 6;153(6):1281-95
references: 23706625
references: Mol Cancer. 2010 Feb 04;9:29
references: 20128929
references: J Cell Biol. 2006 Mar 13;172(6):835-46
references: 16533944
references: BMC Biotechnol. 2004 Dec 24;4:33
references: 15619330
references: Mol Biol Cell. 2012 Feb;23(4):729-39
references: 22190734
references: EMBO J. 2008 Feb 20;27(4):654-66
references: 18219272
references: Cell. 2009 Apr 3;137(1):123-32
references: 19345191
references: Curr Biol. 2007 Apr 3;17(7):630-6
references: 17349791
references: Genome Res. 2013 Aug;23(8):1224-34
references: 23704192
references: Nature. 2009 Jul 16;460(7253):410-3
references: 19458616
references: Curr Biol. 2013 Jan 7;23(1):64-9
references: 23219725
references: Nucleic Acids Res. 2003 Feb 15;31(4):e12
references: 12582257
references: Nat Genet. 2000 Jun;25(2):139-40
references: 10835623
references: J Cell Sci. 2010 Mar 1;123(Pt 5):806-13
references: 20144989
references: Cell. 2000 Oct 27;103(3):399-410
references: 11081627
references: Cell. 2012 Aug 31;150(5):961-74
references: 22901742
references: Curr Biol. 2006 Aug 8;16(15):1571-8
references: 16890534
references: J Cell Biol. 2009 Dec 14;187(6):773-80
references: 19995934
references: Nature. 2008 Jul 17;454(7202):297-301
references: 18596691
references: Cell. 2006 Dec 1;127(5):955-67
references: 17113138
references: Nature. 2011 Aug 03;478(7370):524-8
references: 21814200
references: Nature. 1999 Jul 1;400(6739):37-42
references: 10403247
references: Chromosome Res. 2001;9(1):77-80
references: 11272795
references: Genetics. 2000 Apr;154(4):1693-710
references: 10747063
references: FASEB J. 2000 Mar;14(3):581-92
references: 10698974
references: Nat Methods. 2008 May;5(5):409-15
references: 18391959
references: EMBO J. 2009 May 6;28(9):1234-45
references: 19322193
references: Nature. 2008 Feb 14;451(7180):796-801
references: 18235444
references: Mol Cell. 2011 Oct 7;44(1):97-107
references: 21981921
references: EMBO J. 2013 Mar 6;32(5):666-76
references: 23361318
references: Curr Opin Genet Dev. 2012 Apr;22(2):93-100
references: 22155130
references: J Cell Biol. 2003 Apr 28;161(2):281-94
references: 12707311
references: Nat Methods. 2012 Jul;9(7):671-5
references: 22930834
references: PLoS Genet. 2009 Nov;5(11):e1000739
references: 19956766
references: J Cell Biol. 2006 Mar 13;172(6):847-60
references: 16533945
references: Cell. 2003 Oct 3;115(1):109-21
references: 14532007
references: Cell. 2010 Nov 24;143(5):737-49
references: 21111234
references: Genes Dev. 2008 Nov 15;22(22):3089-114
references: 19056890
references: Nature. 2011 Aug 10;476(7361):467-71
references: 21832993