title: Gain of function mutant p53 proteins cooperate with E2F4 to transcriptionally downregulate RAD17 and BRCA1 gene expression.
abstract: Genomic instability (IN) is a common feature of many human cancers. The TP53 tumour suppressor gene is mutated in approximately half of human cancers. Here, we show that BRCA1 and RAD17 genes, whose derived proteins play a pivotal role in DNA damage repair, are transcriptional targets of gain-of-function mutant p53 proteins. Indeed, high levels of mutp53 protein facilitate DNA damage accumulation and severely impair BRCA1 and RAD17 expression in proliferating cancer cells. The recruitment of mutp53/E2F4 complex onto specific regions of BRCA1 and RAD17 promoters leads to the inhibition of their expression. BRCA1 and RAD17 mRNA expression is reduced in HNSCC patients carrying TP53 mutations when compared to those bearing wt-p53 gene. Furthermore, the analysis of gene expression databases for breast cancer patients reveals that low expression of DNA repair genes correlates significantly with reduced relapse free survival of patients carrying TP53 gene mutations. Collectively, these findings highlight the direct involvement of transcriptionally active gain of function mutant p53 proteins in genomic instability through the impairment of DNA repair mechanisms.
authors: Translational Oncogenomic Unit, Molecular Medicine Area, Regina Elena National Cancer Institute, Rome 00144, Italy.
authors: Fabio
authors: F
authors: Valenti
authors: Translational Oncogenomic Unit, Molecular Medicine Area, Regina Elena National Cancer Institute, Rome 00144, Italy.
authors: Federica
authors: F
authors: Ganci
authors: Translational Oncogenomic Unit, Molecular Medicine Area, Regina Elena National Cancer Institute, Rome 00144, Italy.
authors: Giulia
authors: G
authors: Fontemaggi
authors: Translational Oncogenomic Unit, Molecular Medicine Area, Regina Elena National Cancer Institute, Rome 00144, Italy.
authors: Andrea
authors: A
authors: Sacconi
authors: Molecular Chemoprevention Group, Molecular Medicine Area, Regina Elena National Cancer Institute, Rome 00144, Italy.
authors: Sabrina
authors: S
authors: Strano
authors: Translational Oncogenomic Unit, Molecular Medicine Area, Regina Elena National Cancer Institute, Rome 00144, Italy.
authors: Giovanni
authors: G
authors: Blandino
authors: Translational Oncogenomic Unit, Molecular Medicine Area, Regina Elena National Cancer Institute, Rome 00144, Italy.
authors: Silvia
authors: S
authors: Di Agostino
mesh_terms: D019313:BRCA1 Protein / Q000096:biosynthesis / Q000235:genetics*; D001943:Breast Neoplasms / Q000235:genetics; D018797:Cell Cycle Proteins / Q000096:biosynthesis / Q000235:genetics*; D045744:Cell Line, Tumor; D004249:DNA Damage; D015536:Down-Regulation; D050704:E2F4 Transcription Factor / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D019398:Genes, BRCA1; D016158:Genes, p53; D042822:Genomic Instability; D006258:Head and Neck Neoplasms / Q000235:genetics; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics; D009154:Mutation; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D018797:Cell Cycle Proteins; D050704:E2F4 Transcription Factor; C493762:E2F4 protein, human; C113575:Rad17 protein, human; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53
keywords: BRCA1; DNA damage response; RAD17; gain-of-function; genomic instability; mutant p53
references: Cell Cycle. 2011 Dec 15;10(24):4330-40
references: 22134238
references: Nature. 2004 Nov 18;432(7015):316-23
references: 15549093
references: Ann Oncol. 2013 Dec;24(12):3082-8
references: 24107801
references: Cell. 2002 Jan 25;108(2):171-82
references: 11832208
references: Nat Rev Mol Cell Biol. 2004 Oct;5(10):792-804
references: 15459660
references: J Biol Chem. 2001 Oct 19;276(42):39359-67
references: 11483599
references: Cancer Cell. 2006 Sep;10(3):191-202
references: 16959611
references: Nature. 2005 Apr 14;434(7035):864-70
references: 15829956
references: Proc Natl Acad Sci U S A. 1998 Nov 24;95(24):14066-70
references: 9826654
references: Cancer Cell. 2011 Jul 12;20(1):79-91
references: 21741598
references: Breast Cancer Res Treat. 2009 Dec;118(3):433-41
references: 19052860
references: Clin Cancer Res. 2004 Aug 15;10(16):5367-74
references: 15328174
references: Mol Cell Biol. 2001 Mar;21(5):1874-87
references: 11238924
references: Cancer Res. 2005 Dec 15;65(24):11597-604
references: 16357170
references: J Cell Biochem. 2012 Feb;113(2):433-9
references: 22006292
references: Cell Cycle. 2008 Nov 1;7(21):3440-7
references: 18948736
references: Cancer Biol Ther. 2004 Dec;3(12):1208-11
references: 15662116
references: Nature. 2005 Apr 14;434(7035):907-13
references: 15829965
references: Redox Biol. 2014;2:457-65
references: 24624335
references: J Biol Chem. 2000 Sep 22;275(38):29503-12
references: 10884390
references: PLoS One. 2012;7(1):e30020
references: 22276141
references: Cell. 2000 Jan 7;100(1):57-70
references: 10647931
references: Mol Cell Biol. 1999 Feb;19(2):1438-49
references: 9891077
references: Genes Dev. 2012 Jun 15;26(12):1268-86
references: 22713868
references: Carcinogenesis. 2002 May;23(5):687-96
references: 12016139
references: Head Neck. 2008 Jan;30(1):35-42
references: 17657792
references: Genome Res. 2002 Mar;12(3):458-61
references: 11875034
references: Mol Cell. 2011 Jan 21;41(2):210-20
references: 21195000
references: Science. 2008 Mar 7;319(5868):1352-5
references: 18323444
references: Nat Cell Biol. 2007 May;9(5):573-80
references: 17417627
references: Neoplasia. 2004 Jan-Feb;6(1):1-6
references: 15068665
references: Cell Death Differ. 2014 Sep;21(9):1419-31
references: 24832469
references: Curr Opin Cell Biol. 2007 Apr;19(2):238-45
references: 17303408
references: Nat Cell Biol. 2013 Jan;15(1):2-8
references: 23263379
references: Oncogene. 2003 Aug 28;22(36):5667-76
references: 12944915
references: Cancer Cell. 2010 Mar 16;17(3):273-85
references: 20227041
references: J Clin Invest. 2007 Jul;117(7):1893-901
references: 17607363
references: Cell. 2012 Jan 20;148(1-2):244-58
references: 22265415
references: OMICS. 2011 May;15(5):305-12
references: 21332394
references: Cancer Res. 2007 Mar 15;67(6):2396-401
references: 17363555
references: Oncogene. 2002 Jan 17;21(3):356-67
references: 11821948
references: Mol Cell Biol. 2011 Nov;31(22):4464-81
references: 21930790
references: OMICS. 2011 Jun;15(6):375-81
references: 21348641
references: Breast Cancer Res. 2003;5(1):45-52
references: 12559046
references: Nat Rev Mol Cell Biol. 2010 Mar;11(3):220-8
references: 20177397
references: Nature. 2013 Oct 17;502(7471):333-9
references: 24132290
references: Genet Mol Biol. 2010 Apr;33(2):368-73
references: 21637496
references: Int J Cancer. 2010 Dec 15;127(12):2893-917
references: 21351269
references: Mol Cell. 2007 May 25;26(4):539-51
references: 17531812
references: Cancer Cell. 2005 May;7(5):469-83
references: 15894267
references: Nat Struct Mol Biol. 2009 Oct;16(10):1086-93
references: 19783986
references: Cell. 2004 Dec 17;119(6):847-60
references: 15607980
references: PLoS Genet. 2012;8(11):e1003027
references: 23173005
references: Proc Natl Acad Sci U S A. 2003 Sep 30;100(20):11547-52
references: 12972634
references: J Biol Chem. 2002 May 24;277(21):18817-26
references: 11893750
references: Cell Cycle. 2006 Sep;5(17):1940-5
references: 16940754
references: Int J Cancer. 2000 Jun 1;86(5):672-7
references: 10797289
references: World J Gastroenterol. 2005 Jul 14;11(26):4102-7
references: 15996039
references: FASEB J. 2000 Nov;14(14):2291-302
references: 11053251
references: Breast Cancer Res. 2007;9(3):R30
references: 17504517
references: Proc Natl Acad Sci U S A. 2001 Sep 11;98(19):10869-74
references: 11553815
references: Science. 2011 Aug 26;333(6046):1157-60
references: 21798893
references: Int J Oncol. 2006 Aug;29(2):495-501
references: 16820894