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Gain of function mutant p53 proteins cooperate with E2F4 to transcriptionally downregulate RAD17 and BRCA1 gene expression
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Fabio Valenti1, Federica Ganci1, Giulia Fontemaggi1, Andrea Sacconi1, Sabrina Strano2, Giovanni Blandino1, Silvia Di Agostino1
1Translational Oncogenomic Unit, Molecular Medicine Area, Regina Elena National Cancer Institute, Rome 00144, Italy
2Molecular Chemoprevention Group, Molecular Medicine Area, Regina Elena National Cancer Institute, Rome 00144, Italy
Giovanni Blandino, e-mail: [email protected]
Silvia Di Agostino, e-mail: [email protected]
Keywords: mutant p53, gain-of-function, genomic instability, DNA damage response, BRCA1, RAD17
Received: September 05, 2014 Accepted: October 10, 2014 Published: February 05, 2015
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.
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