title: Gcn5 and SAGA regulate shelterin protein turnover and telomere maintenance.
abstract: Histone acetyltransferases (HATs) play important roles in gene regulation and DNA repair by influencing the accessibility of chromatin to transcription factors and repair proteins. Here, we show that deletion of Gcn5 leads to telomere dysfunction in mouse and human cells. Biochemical studies reveal that depletion of Gcn5 or ubiquitin-specific protease 22 (Usp22), which is another bona fide component of the Gcn5-containing SAGA complex, increases ubiquitination and turnover of TRF1, a primary component of the telomeric shelterin complex. Inhibition of the proteasome or overexpression of USP22 opposes this effect. The USP22 deubiquitinating module requires association with SAGA complexes for activity, and we find that depletion of Gcn5 compromises this association in mammalian cells. Thus, our results indicate that Gcn5 regulates TRF1 levels through effects on Usp22 activity and SAGA integrity.
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Texas M.D. Anderson Cancer Center, Houston, 77030, USA.
authors.forename: Boyko S
authors.initials: BS
authors.lastname: Atanassov
authors.forename: Yvonne A
authors.initials: YA
authors.lastname: Evrard
authors.forename: Asha S
authors.initials: AS
authors.lastname: Multani
authors.forename: Zhijing
authors.initials: Z
authors.lastname: Zhang
authors.forename: László
authors.initials: L
authors.lastname: Tora
authors.forename: Didier
authors.initials: D
authors.lastname: Devys
authors.forename: Sandy
authors.initials: S
authors.lastname: Chang
authors.forename: Sharon Y R
authors.initials: SY
authors.lastname: Dent
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D002869:Chromosome Aberrations; D053903:DNA Breaks, Double-Stranded; D004260:DNA Repair / Q000235:genetics; D017353:Gene Deletion; D006801:Humans; D051379:Mice; D008954:Models, Biological; D061988:Proteasome Inhibitors; D055550:Protein Stability; D000089804:Shelterin Complex; D016615:Telomere / Q000378:metabolism*; D034501:Telomere-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D035321:Telomeric Repeat Binding Protein 1 / Q000235:genetics / Q000378:metabolism*; D013869:Thiolester Hydrolases / Q000235:genetics / Q000378:metabolism*; D043222:Ubiquitin Thiolesterase; D050880:p300-CBP Transcription Factors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D000099224:p300-CBP-Associated Factor
chemical_list: D061988:Proteasome Inhibitors; D000089804:Shelterin Complex; D034501:Telomere-Binding Proteins; D035321:Telomeric Repeat Binding Protein 1; D013869:Thiolester Hydrolases; D043222:Ubiquitin Thiolesterase; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor; C440849:POT1 protein, human; C527170:Usp22 protein, human
references.citation: J Biol Chem. 2008 Dec 5;283(49):33808-15
references.pmid: 18838386
references.citation: Mol Cell Biol. 1996 Feb;16(2):593-602
references.pmid: 8552087
references.citation: EMBO J. 2007 Nov 14;26(22):4709-19
references.pmid: 17948054
references.citation: Mol Cell Biol. 2002 Jul;22(13):4723-38
references.pmid: 12052880
references.citation: J Biol Chem. 1996 Mar 1;271(9):5237-45
references.pmid: 8617808
references.citation: Nature. 2003 Nov 13;426(6963):194-8
references.pmid: 14608368
references.citation: Proc Natl Acad Sci U S A. 2000 Oct 10;97(21):11303-6
references.pmid: 11027331
references.citation: J Biol Chem. 2008 Aug 29;283(35):23981-8
references.pmid: 18587156
references.citation: J Biol Chem. 2006 Jan 13;281(2):759-68
references.pmid: 16275645
references.citation: EMBO J. 2001 Oct 1;20(19):5532-40
references.pmid: 11574485
references.citation: Cell. 2004 Jan 9;116(1):75-86
references.pmid: 14718168
references.citation: Mol Biol Cell. 2006 Oct;17(10):4228-36
references.pmid: 16855026
references.citation: Mol Cell Biol. 2005 Feb;25(3):1173-82
references.pmid: 15657442
references.citation: Mol Cell Biol. 2001 Oct;21(20):6782-95
references.pmid: 11564863
references.citation: Cell. 1996 Mar 22;84(6):843-51
references.pmid: 8601308
references.citation: Nature. 1997 Feb 20;385(6618):740-3
references.pmid: 9034193
references.citation: Nature. 1996 Jul 25;382(6589):319-24
references.pmid: 8684459
references.citation: Genes Dev. 1997 Jul 1;11(13):1640-50
references.pmid: 9224714
references.citation: Mol Cell. 2004 Jul 23;15(2):199-208
references.pmid: 15260971
references.citation: Gene Expr Patterns. 2006 Mar;6(3):277-84
references.pmid: 16378762
references.citation: Annu Rev Biochem. 2001;70:81-120
references.pmid: 11395403
references.citation: Mol Cell Biol. 2005 Feb;25(3):1162-72
references.pmid: 15657441
references.citation: Nat Rev Mol Cell Biol. 2007 Apr;8(4):284-95
references.pmid: 17380162
references.citation: Trends Biochem Sci. 2008 Aug;33(8):369-75
references.pmid: 18603431
references.citation: J Biol Chem. 2004 Jan 16;279(3):1867-71
references.pmid: 14660634
references.citation: Mol Biol Cell. 2008 Sep;19(9):3616-24
references.pmid: 18562693
references.citation: Dev Dyn. 2007 Jun;236(6):1547-57
references.pmid: 17440986
references.citation: J Biol Chem. 2007 Aug 3;282(31):22662-7
references.pmid: 17561506
references.citation: Mol Cell. 2008 Jan 18;29(1):102-11
references.pmid: 18206973
references.citation: Nature. 2007 Aug 30;448(7157):1068-71
references.pmid: 17687332
references.citation: Genes Dev. 2005 Sep 15;19(18):2100-10
references.pmid: 16166375
references.citation: Nat Cell Biol. 2008 Jun;10(6):707-15
references.pmid: 18488019
references.citation: Mol Cell Biol. 2004 Aug;24(16):7249-59
references.pmid: 15282323
references.citation: Oncogene. 2007 Aug 13;26(37):5341-57
references.pmid: 17694077
references.citation: Mol Cell Biol. 2007 May;27(9):3405-16
references.pmid: 17325035
references.citation: Science. 1998 Nov 20;282(5393):1484-7
references.pmid: 9822378
references.citation: J Biol Chem. 2009 Mar 27;284(13):8557-66
references.pmid: 19164295
references.citation: Genes Dev. 2003 Jun 1;17(11):1328-33
references.pmid: 12782650
references.citation: Oncogene. 2002 Jan 21;21(4):532-40
references.pmid: 11850778
references.citation: Cell. 2000 Aug 18;102(4):463-73
references.pmid: 10966108
references.citation: Cell Cycle. 2006 Jun;5(11):1208-16
references.pmid: 16760651
references.citation: Genes Dev. 2003 Nov 1;17(21):2648-63
references.pmid: 14563679
references.citation: J Mol Biol. 1998 Apr 24;278(1):79-88
references.pmid: 9571035
references.citation: Nat Genet. 2001 Oct;29(2):206-11
references.pmid: 11544477
references.citation: EMBO J. 2008 Jan 23;27(2):394-405
references.pmid: 18188155
references.citation: Results Probl Cell Differ. 2006;41:109-25
references.pmid: 16909893
references.citation: Dev Dyn. 2008 Apr;237(4):928-40
references.pmid: 18330926
references.citation: Mol Cell Biol. 1998 Oct;18(10):5659-69
references.pmid: 9742083
references.citation: Proteomics. 2003 Feb;3(2):217-23
references.pmid: 12601814
references.citation: Nat Cell Biol. 2006 Jan;8(1):91-9
references.pmid: 16341205
references.citation: J Biol Chem. 2004 Jan 9;279(2):1442-8
references.pmid: 14559908
references.citation: Cell. 2006 Jul 14;126(1):49-62
references.pmid: 16839876
references.citation: Neuron. 2001 Jan;29(1):99-113
references.pmid: 11182084
references.citation: Nat Genet. 2000 Oct;26(2):229-32
references.pmid: 11017084
references.citation: Mol Cell. 2008 Jan 18;29(1):92-101
references.pmid: 18206972
references.citation: EMBO J. 1998 Jun 1;17(11):3155-67
references.pmid: 9606197
references.citation: Mol Cell Biol. 1999 Jan;19(1):86-98
references.pmid: 9858534
references.citation: Cell. 2007 Nov 16;131(4):633-6
references.pmid: 18022353
references.citation: Proc Natl Acad Sci U S A. 1999 Aug 3;96(16):8931-6
references.pmid: 10430873