Understanding the role of E2F7 in the regulation of cellular proliferation and DNA damage responses

Resumen

E2F transcription factors control diverse biological processes through regulation of target gene expression. The identification of a large set of genes regulated by each individual E2F, including those coding for microRNAs, has led to a better understanding of the functions performed by the different members of the family. Many studies have detailed the role of classical E2Fs in cell cycle control and DNA damage response. By contrast, the contribution of the atypical members of the family, E2F7 and E2F8, to these processes has not been clearly defined. A recent study from our group identified a set of novel microRNAs and protein-coding genes regulated by E2F7. These genes are involved in processes such as cell cycle regulation or DNA damage response. In this work, we have examined the role that E2F7 plays in the regulation of these processes through the transcriptional regulation of its target genes. We have identified E2F7 as a transcription factor required for the repression of a set of microRNAs that promote cellular proliferation. We show that miR-25, miR-92 and miR-7 expression is controlled at the transcriptional level by the antagonistic activity of E2F7 and E2F1-3. Interestingly, we find that several E2F7-repressed microRNAs downregulate the expression of cell cycle progression inhibitors and promote cellular proliferation, suggesting that E2F7 restrains cell cycle progression through repression of proliferation-promoting microRNAs.Importantly, we show that E2F7 plays a key role in the maintenance of genomic stability. We present evidence of E2F7-dependent transcriptional and non-transcriptional mechanisms for modulating cellular responses to genotoxic exposure. We identify an E2F7-dependent transcriptional regulation program that restricts homologous recombination-mediated DNA repair and cellular recovery upon induction of DNA lesions that interfere with replication fork progression (DNA interstrand cross-links and PARP1 inhibition).Additionally, we present evidence of a non-transcriptional mechanism by which E2F7 modulates cellular responses to alkylating DNA damage, possibly involving interaction with the repair protein XRRC1. Loss of E2F7 confers an increased resistance to chemotherapy in homologous recombination-deficient cells, a potentially harmful outcome for cancer treatment. Altogether, results in this work reveal a key role for E2F7 in limiting cellular proliferation and promoting genomic stability by ensuring the timely expression of protein-coding and microRNA genes that are required for cell cycle progression and DNA damage repair.