Gain of function mutant p53 proteins cooperate with E2F4 to transcriptionally downregulate RAD17 and BRCA1 gene expression.

Fabio Valenti,Giovanni Blandino,Silvia Di Agostino,Federica Ganci,Sabrina Strano,Giulia Fontemaggi,Andrea Sacconi

doi:10.18632/oncotarget.2587

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.

Highlights

Upon DNA insults, stabilization of the tumour suppressor p53 leads to transcription of genes involved in cell cycle arrest, senescence, DNA repair and apoptosis to prevent accumulation of unrepaired DNA and propagation of mutated DNA [1,2,3]
We explored the molecular mechanisms that underlie the inactivation of DNA repair genes in mutp53-expressing tumour cells
We show that mutp53 physically interacted with the transcription factor E2F4 that is a component of the DREAM repressor complex [44]

Summary

Introduction

Upon DNA insults, stabilization of the tumour suppressor p53 leads to transcription of genes involved in cell cycle arrest, senescence, DNA repair and apoptosis to prevent accumulation of unrepaired DNA and propagation of mutated DNA [1,2,3]. P53 mutations disrupt wt-p53 tumour suppressive functions and confer new oncogenic properties (GOF) that contribute to growth advantage of tumour cells [2, 3]. Concerning the molecular mechanisms through which mutp proteins exert their oncogenic functions, we and others previously characterized their ability to modulate gene expression through interaction with other transcription factors, such as NF-Y, E2F1, NF-kB, ZEB1, SP1, ETS1 and VDR [3, 9,10,11,12,13,14,15]. Mutp proteins bind to p53 family members, p63 and p73 impairing their transcriptional activity and their anti-tumoural effects [16,17,18,19]. We documented the existence of an oncogenic autoregulatory feedback loop that includes the Polo-like kinase (Snk/Plk2), a regulator of centrosomal checkpoint, and mutp proteins where Plk binds to and phosphorylates mutp, thereby potentiating its oncogenic activities [20]

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