title: Characterization of the p53 cistrome--DNA binding cooperativity dissects p53's tumor suppressor functions.
abstract: p53 protects us from cancer by transcriptionally regulating tumor suppressive programs designed to either prevent the development or clonal expansion of malignant cells. How p53 selects target genes in the genome in a context- and tissue-specific manner remains largely obscure. There is growing evidence that the ability of p53 to bind DNA in a cooperative manner prominently influences target gene selection with activation of the apoptosis program being completely dependent on DNA binding cooperativity. Here, we used ChIP-seq to comprehensively profile the cistrome of p53 mutants with reduced or increased cooperativity. The analysis highlighted a particular relevance of cooperativity for extending the p53 cistrome to non-canonical binding sequences characterized by deletions, spacer insertions and base mismatches. Furthermore, it revealed a striking functional separation of the cistrome on the basis of cooperativity; with low cooperativity genes being significantly enriched for cell cycle and high cooperativity genes for apoptotic functions. Importantly, expression of high but not low cooperativity genes was correlated with superior survival in breast cancer patients. Interestingly, in contrast to most p53-activated genes, p53-repressed genes did not commonly contain p53 binding elements. Nevertheless, both the degree of gene activation and repression were cooperativity-dependent, suggesting that p53-mediated gene repression is largely indirect and mediated by cooperativity-dependently transactivated gene products such as CDKN1A, E2F7 and non-coding RNAs. Since both activation of apoptosis genes with non-canonical response elements and repression of pro-survival genes are crucial for p53's apoptotic activity, the cistrome analysis comprehensively explains why p53-induced apoptosis, but not cell cycle arrest, strongly depends on the intermolecular cooperation of p53 molecules as a possible safeguard mechanism protecting from accidental cell killing.
authors: Molecular Oncology, Philipps-University, Marburg, Germany.
authors: Katharina
authors: K
authors: Schlereth
authors: Charlotte
authors: C
authors: Heyl
authors: Anna-Maria
authors: AM
authors: Krampitz
authors: Marco
authors: M
authors: Mernberger
authors: Florian
authors: F
authors: Finkernagel
authors: Maren
authors: M
authors: Scharfe
authors: Michael
authors: M
authors: Jarek
authors: Ellen
authors: E
authors: Leich
authors: Andreas
authors: A
authors: Rosenwald
authors: Thorsten
authors: T
authors: Stiewe
mesh_terms: D017209:Apoptosis / Q000235:genetics*; D001483:Base Sequence; D001665:Binding Sites / Q000235:genetics; D059447:Cell Cycle Checkpoints / Q000235:genetics*; D002455:Cell Division; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D004249:DNA Damage / Q000235:genetics; D050702:E2F7 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism; D011485:Protein Binding / Q000235:genetics; D022661:RNA, Untranslated / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism
chemical_list: C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D050702:E2F7 Transcription Factor; C481054:E2F7 protein, human; D022661:RNA, Untranslated; D016159:Tumor Suppressor Protein p53
references: Cell. 2011 Feb 4;144(3):327-39
references: 21295696
references: Proc Natl Acad Sci U S A. 2005 Sep 20;102(38):13550-5
references: 16141321
references: Biophys Chem. 2002 Dec 10;101-102:611-23
references: 12488030
references: BMC Bioinformatics. 2006 Sep 06;7 Suppl 2:S13
references: 17118134
references: Mol Cell. 2003 Oct;12(4):1015-27
references: 14580351
references: BMC Genomics. 2008 Oct 15;9:486
references: 18922183
references: Oncogene. 2007 Nov 15;26(52):7363-70
references: 17563751
references: Mol Cell. 2001 Oct;8(4):781-94
references: 11684014
references: J Comput Biol. 1998 Summer;5(2):211-21
references: 9672829
references: J Mol Biol. 2004 Aug 27;341(5):1145-59
references: 15321712
references: Bioinformatics. 2011 Jun 15;27(12):1696-7
references: 21486936
references: EMBO Rep. 2012 Apr 10;13(5):423-30
references: 22491032
references: Bioinformatics. 2011 Apr 1;27(7):1017-8
references: 21330290
references: Genome Biol. 2009;10(3):R25
references: 19261174
references: Cell. 2010 Aug 6;142(3):409-19
references: 20673990
references: Nature. 2009 Jul 23;460(7254):529-33
references: 19626115
references: Cell Cycle. 2010 Oct 15;9(20):4068-76
references: 20948308
references: Nat Rev Mol Cell Biol. 2007 Apr;8(4):275-83
references: 17380161
references: PLoS One. 2011 Mar 04;6(3):e17574
references: 21394211
references: Lancet. 2002 Sep 14;360(9336):852-4
references: 12243922
references: PLoS Genet. 2007 Jul;3(7):e127
references: 17677004
references: Nat Rev Cancer. 2012 Sep;12(9):613-26
references: 22898542
references: Science. 2004 Feb 6;303(5659):844-8
references: 14704432
references: Genes Dev. 2012 Jul 15;26(14):1546-57
references: 22802529
references: Nucleic Acids Res. 2011 Mar;39(5):1919-32
references: 21071400
references: Bioinformatics. 2006 Dec 1;22(23):2926-33
references: 17000751
references: Lancet. 1995 May 6;345(8958):1182
references: 7723572
references: J Biol Chem. 2003 Aug 29;278(35):32507-16
references: 12748190
references: Genes Dev. 2012 Jul 15;26(14):1533-45
references: 22802528
references: Nat Rev Mol Cell Biol. 2008 May;9(5):402-12
references: 18431400
references: Mol Cell. 2007 Jun 8;26(5):745-52
references: 17540599
references: Nat Rev Cancer. 2007 Mar;7(3):165-8
references: 17332760
references: Trends Cell Biol. 2011 Jun;21(6):344-53
references: 21601459
references: Proc Natl Acad Sci U S A. 2008 Jan 22;105(3):944-9
references: 18187580
references: Proc Natl Acad Sci U S A. 2010 Dec 28;107(52):22745-50
references: 21149740
references: Cell. 2009 May 1;137(3):413-31
references: 19410540
references: Cancer Cell. 2009 May 5;15(5):441-53
references: 19411072
references: Mol Cell. 2006 Jun 23;22(6):741-753
references: 16793544
references: Cancer Res. 2008 Dec 1;68(23):9671-7
references: 19047144
references: Proc Natl Acad Sci U S A. 2006 Jan 31;103(5):1406-11
references: 16432214
references: Nat Genet. 1996 Dec;14(4):482-6
references: 8944033
references: Cell Rep. 2013 May 30;3(5):1512-25
references: 23665223
references: Cold Spring Harb Perspect Biol. 2010 Aug;2(8):a000935
references: 20679336
references: Nature. 2012 Sep 6;489(7414):57-74
references: 22955616
references: Mol Cell. 2007 Jun 8;26(5):731-43
references: 17540598
references: Science. 1994 Jul 15;265(5170):346-55
references: 8023157
references: Mol Cell. 2012 Apr 13;46(1):30-42
references: 22387025
references: Proc Natl Acad Sci U S A. 2002 Jun 25;99(13):8467-72
references: 12077306
references: Angew Chem Int Ed Engl. 2005 Aug 19;44(33):5247-51
references: 16035029
references: Proc Natl Acad Sci U S A. 2005 Oct 25;102(43):15545-50
references: 16199517
references: Nat Genet. 2002 Mar;30(3):315-20
references: 11919562
references: J Mol Biol. 2005 May 6;348(3):589-96
references: 15826656
references: Science. 1996 Nov 8;274(5289):1001-5
references: 8875926
references: Mol Cell Biol. 2005 Sep;25(17):7423-31
references: 16107691
references: Cell. 1993 Nov 19;75(4):817-25
references: 8242752
references: J Biol Chem. 2001 Dec 28;276(52):49020-7
references: 11606582
references: PLoS Genet. 2008 Jun 27;4(6):e1000104
references: 18714371
references: BMC Cancer. 2006 Dec 06;6:276
references: 17150101
references: Cell. 2006 Jan 13;124(1):207-19
references: 16413492
references: Mol Cell Biol. 2007 Apr;27(7):2590-600
references: 17242190
references: Nature. 2007 Jun 28;447(7148):1130-4
references: 17554337
references: Cancer Cell. 2012 Jun 12;21(6):793-806
references: 22698404
references: N Engl J Med. 2002 Dec 19;347(25):1999-2009
references: 12490681
references: Proc Natl Acad Sci U S A. 1995 Sep 12;92(19):8591-5
references: 7567980
references: Mol Cell. 2010 May 14;38(3):356-68
references: 20471942
references: Cell. 2011 May 13;145(4):571-83
references: 21565614
references: Nature. 2000 Nov 16;408(6810):307-10
references: 11099028
references: Genome Biol. 2007;8(2):R24
references: 17324271
references: Nat Rev Cancer. 2009 Oct;9(10):724-37
references: 19776742
references: Cell Death Differ. 2012 Dec;19(12):1992-2002
references: 22790872
references: PLoS Med. 2007 Mar;4(3):e90
references: 17388661