title: Acetylation limits 53BP1 association with damaged chromatin to promote homologous recombination.
abstract: The pathogenic sequelae of BRCA1 mutation in human and mouse cells are mitigated by concomitant deletion of 53BP1, which binds histone H4 dimethylated at Lys20 (H4K20me2) to promote nonhomologous end joining, suggesting that a balance between BRCA1 and 53BP1 regulates DNA double strand-break (DSB) repair mechanism choice. Here we document that acetylation is a key determinant of this balance. TIP60 acetyltransferase deficiency reduced BRCA1 at DSB chromatin with commensurate increases in 53BP1, whereas HDAC inhibition yielded the opposite effect. TIP60-dependent H4 acetylation diminished 53BP1 binding to H4K20me2 in part through disruption of a salt bridge between H4K16 and Glu1551 in the 53BP1 Tudor domain. Moreover, TIP60 deficiency impaired homologous recombination and conferred sensitivity to PARP inhibition in a 53BP1-dependent manner. These findings demonstrate that acetylation in cis to H4K20me2 regulates relative BRCA1 and 53BP1 DSB chromatin occupancy to direct DNA repair mechanism.
authors: Department of Cancer Biology, Abramson Family Cancer Research Institute, Basser Research Center for BRCA, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors: Jiangbo
authors: J
authors: Tang
authors: Nam Woo
authors: NW
authors: Cho
authors: Gaofeng
authors: G
authors: Cui
authors: Erica M
authors: EM
authors: Manion
authors: Niraj M
authors: NM
authors: Shanbhag
authors: Maria Victoria
authors: MV
authors: Botuyan
authors: Georges
authors: G
authors: Mer
authors: Roger A
authors: RA
authors: Greenberg
mesh_terms: D000074183:ATPases Associated with Diverse Cellular Activities; D000107:Acetylation; D000595:Amino Acid Sequence; D019313:BRCA1 Protein / Q000235:genetics / Q000378:metabolism*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D002843:Chromatin / Q000235:genetics / Q000378:metabolism*; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics / Q000378:metabolism; D053903:DNA Breaks, Double-Stranded; D004265:DNA Helicases / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D055785:Gene Knockdown Techniques; D051548:Histone Acetyltransferases / Q000235:genetics / Q000378:metabolism; D006655:Histone Deacetylases / Q000378:metabolism; D006657:Histones / Q000378:metabolism*; D059765:Homologous Recombination; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D000074443:Lysine Acetyltransferase 5; D009682:Magnetic Resonance Spectroscopy; D008969:Molecular Sequence Data; D011487:Protein Conformation; D000071857:Tumor Suppressor p53-Binding Protein 1
chemical_list: D019313:BRCA1 Protein; D002352:Carrier Proteins; D002843:Chromatin; D002868:Chromosomal Proteins, Non-Histone; D004268:DNA-Binding Proteins; D006657:Histones; D047908:Intracellular Signaling Peptides and Proteins; C498301:TP53BP1 protein, human; C498302:Trp53bp1 protein, mouse; D000071857:Tumor Suppressor p53-Binding Protein 1; D051548:Histone Acetyltransferases; C098489:KAT5 protein, human; D000074443:Lysine Acetyltransferase 5; D006655:Histone Deacetylases; D000074183:ATPases Associated with Diverse Cellular Activities; D004265:DNA Helicases; C486549:RUVBL1 protein, human
references: J Cell Biol. 2004 May 24;165(4):459-64
references: 15159415
references: Mol Cell. 2012 Aug 24;47(4):497-510
references: 22920291
references: Biochemistry. 2009 May 12;48(18):3798-800
references: 19334741
references: Mol Cell Biol. 2005 Sep;25(18):8179-90
references: 16135807
references: Methods Mol Biol. 2004;278:353-78
references: 15318003
references: Nature. 2004 Nov 18;432(7015):406-11
references: 15525939
references: Nat Cell Biol. 2006 Jan;8(1):91-9
references: 16341205
references: Nature. 1997 Sep 18;389(6648):251-60
references: 9305837
references: Nat Struct Mol Biol. 2010 Jun;17(6):688-95
references: 20453858
references: Cell. 2009 Feb 6;136(3):420-34
references: 19203578
references: Cell. 1998 Aug 21;94(4):439-49
references: 9727487
references: Mol Cell Biol. 2005 Jun;25(12):4903-13
references: 15923609
references: Nat Struct Mol Biol. 2011 Nov 27;18(12):1345-50
references: 22120668
references: J Comput Chem. 2005 Dec;26(16):1668-88
references: 16200636
references: Nat Immunol. 2004 May;5(5):481-7
references: 15077110
references: Science. 2007 May 25;316(5828):1194-8
references: 17525340
references: Mol Cell. 2011 May 6;42(3):319-29
references: 21549309
references: Nat Genet. 2001 Jul;28(3):266-71
references: 11431698
references: J Cell Biol. 2007 Jul 2;178(1):9-14
references: 17591918
references: Cell. 2010 Jun 11;141(6):970-81
references: 20550933
references: Nat Genet. 2005 Apr;37(4):391-400
references: 15765097
references: Nucleic Acids Res. 2011 Jan;39(Database issue):D876-82
references: 20959295
references: Nat Struct Mol Biol. 2010 Sep;17(9):1144-51
references: 20802485
references: Science. 2007 May 25;316(5828):1198-202
references: 17525341
references: Cell. 2006 Dec 29;127(7):1361-73
references: 17190600
references: Nature. 2005 Apr 14;434(7035):917-21
references: 15829967
references: Mol Cell Biol. 2008 Jan;28(1):468-86
references: 17967882
references: N Engl J Med. 2009 Jul 9;361(2):123-34
references: 19553641
references: Cell. 2007 Nov 30;131(5):901-14
references: 18001825
references: Cell. 2004 Mar 5;116(5):683-98
references: 15006351
references: Nature. 2005 Apr 14;434(7035):913-7
references: 15829966
references: Nature. 2009 May 21;459(7245):460-3
references: 19357644
references: Cell. 2012 Aug 17;150(4):697-709
references: 22884692
references: Science. 2007 Dec 7;318(5856):1637-40
references: 18006705
references: Nature. 2012 Mar 07;484(7392):115-9
references: 22398447
references: Trends Biochem Sci. 2012 Oct;37(10):418-24
references: 22836122
references: Cell. 2000 Aug 18;102(4):463-73
references: 10966108
references: Cell. 2007 Nov 30;131(5):887-900
references: 18001824
references: Cell. 2007 Mar 9;128(5):1003-12
references: 17350582
references: Mol Cell. 1999 Oct;4(4):511-8
references: 10549283
references: Science. 2007 May 25;316(5828):1202-5
references: 17525342
references: J Biomol NMR. 1996 Dec;8(4):477-86
references: 9008363
references: Mol Cell. 2010 Nov 12;40(3):364-76
references: 21035370
references: Cell. 2009 Feb 6;136(3):435-46
references: 19203579
references: Nature. 2008 Nov 27;456(7221):524-8
references: 18931659
references: Cell. 2004 Nov 24;119(5):603-14
references: 15550243
references: J Cell Biol. 2009 Nov 2;187(3):319-26
references: 19948475
references: Mol Cell Biol. 2008 Apr;28(8):2690-700
references: 18285460
references: J Biol Chem. 2008 Mar 21;283(12):7713-20
references: 18171670
references: Nature. 2007 Aug 30;448(7157):1063-7
references: 17728759
references: Science. 2006 Feb 10;311(5762):844-7
references: 16469925
references: J Cell Sci. 2012 Aug 1;125(Pt 15):3529-34
references: 22553214
references: EMBO J. 2012 Apr 18;31(8):1865-78
references: 22373579
references: Science. 2009 May 1;324(5927):602-3
references: 19407191
references: J Cell Biol. 2012 Apr 16;197(2):189-99
references: 22492721
references: Cell. 2010 Apr 16;141(2):243-54
references: 20362325