The atypical E2F family member E2F7 couples the p53 and RB pathways during cellular senescence

Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
Genes & development (Impact Factor: 10.8). 07/2012; 26(14):1546-57. DOI: 10.1101/gad.196238.112
Source: PubMed


Oncogene-induced senescence is an anti-proliferative stress response program that acts as a fail-safe mechanism to limit oncogenic transformation and is regulated by the retinoblastoma protein (RB) and p53 tumor suppressor pathways. We identify the atypical E2F family member E2F7 as the only E2F transcription factor potently up-regulated during oncogene-induced senescence, a setting where it acts in response to p53 as a direct transcriptional target. Once induced, E2F7 binds and represses a series of E2F target genes and cooperates with RB to efficiently promote cell cycle arrest and limit oncogenic transformation. Disruption of RB triggers a further increase in E2F7, which induces a second cell cycle checkpoint that prevents unconstrained cell division despite aberrant DNA replication. Mechanistically, E2F7 compensates for the loss of RB in repressing mitotic E2F target genes. Together, our results identify a causal role for E2F7 in cellular senescence and uncover a novel link between the RB and p53 pathways.

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Available from: Xiaowo Wang, Aug 26, 2015
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    • "Our expression analyses revealed many more genes repressed in a TP53-dependent manner in response to genotoxic stress, in particular, to cisplatin treatment. These effects are likely influenced both directly through TP53-induced binding and indirectly through downstream effects of known TP53 targets CDKN1A or E2F7 (66) or indeed TP63 inactivation as demonstrated here. We did observe TP53 binding sites frequently associated with more distal TP53 binding events in enhancer-like elements the majority of which are associated with TP63 binding in untreated cells. "
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    ABSTRACT: In response to genotoxic stress the TP53 tumour suppressor activates target gene expression to induce cell cycle arrest or apoptosis depending on the extent of DNA damage. These canonical activities can be repressed by TP63 in normal stratifying epithelia to maintain proliferative capacity or drive proliferation of squamous cell carcinomas, where TP63 is frequently overexpressed/amplified. Here we use ChIP-sequencing, integrated with microarray analysis, to define the genome-wide interplay between TP53 and TP63 in response to genotoxic stress in normal cells. We reveal that TP53 and TP63 bind to overlapping, but distinct cistromes of sites through utilization of distinctive consensus motifs and that TP53 is constitutively bound to a number of sites. We demonstrate that cisplatin and adriamycin elicit distinct effects on TP53 and TP63 binding events, through which TP53 can induce or repress transcription of an extensive network of genes by direct binding and/or modulation of TP63 activity. Collectively, this results in a global TP53-dependent repression of cell cycle progression, mitosis and DNA damage repair concomitant with activation of anti-proliferative and pro-apoptotic canonical target genes. Further analyses reveal that in the absence of genotoxic stress TP63 plays an important role in maintaining expression of DNA repair genes, loss of which results in defective repair.
    Nucleic Acids Research 05/2014; 42(10). DOI:10.1093/nar/gku299 · 9.11 Impact Factor
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    • "Together with our data on hTERT re-introduction, this confirms that replicative senescence is not a completely autonomous program, but a specialized cell cycle arrest that occurs in response to nonrepairable DNA damage, mostly at telomeric regions. Global gene expression regulation during senescence has been the topic of previous studies, but the combination of analysis presented in our study is unique, especially as many published studies either use oncogene-induced senescence (Chicas et al., 2010; Aksoy et al., 2012) as model for senescence or grow cells at atmospheric oxygen levels (Kim et al., 2013), both of which dramatically alter gene expression programs. "
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    ABSTRACT: Replicative senescence is a fundamental tumor-suppressive mechanism triggered by telomere erosion that results in a permanent cell cycle arrest. To understand the impact of telomere shortening on gene expression, we analyzed the transcriptome of diploid human fibroblasts as they progressed toward and entered into senescence. We distinguished novel transcription regulation due to replicative senescence by comparing senescence-specific expression profiles to profiles from cells arrested by DNA damage or serum starvation. Only a small specific subset of genes was identified that was truly senescence-regulated and changes in gene expression were exacerbated from presenescent to senescent cells. The majority of gene expression regulation in replicative senescence was shown to occur due to telomere shortening, as exogenous telomerase activity reverted most of these changes.
    Aging cell 05/2014; 13(5). DOI:10.1111/acel.12234 · 6.34 Impact Factor
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    • "E2F7 has recently been identified as a p53-responsive E2F family member that is activated during DNA damage response [17, 18]. E2F7 has also been identified as the repressor that regulates E2F1 expression [16-18]. "
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    ABSTRACT: C-terminal binding protein (CtBP) family transcriptional corepressors include CtBP1 and CtBP2. While CtBP1 and CtBP2 share significant amino acid sequence homology, CtBP2 possesses a unique N-terminal domain that is modified by acetylation and contributes to exclusive nuclear localization. Although CtBP1 and CtBP2 are functionally redundant for certain activities during vertebrate development, they also perform unique functions. Previous studies have identified several CtBP1-interacting proteins that included other transcriptional corepressors, DNA-binding repressors and histone modifying enzymatic components such as the histone deacetylases and the histone demethylase LSD-1. Here, we carried out an unbiased proteomic analysis of CtBP2-associated proteins and discovered the association of several components of the CtBP1 proteome as well as novel interactions. The CtBP2 proteome contained components of the NuRD complex and the E2F family member E2F7. E2F7 interacted with the hydrophobic cleft region of CtBP1 and CtBP2 through a prototypical CtBP binding motif, PIDLS. E2F7 repressed E2F1 transcription, inhibited cell proliferation in a CtBP-dependent fashion. Our study identified CtBP as a corepressor of E2F7 and as a regulator of DNA damage response.
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