A new role for E2F1 in DNA repair

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E2F1 promotes the recruitment of DNA repair factors to sites of DNA double-strand breaks

E2F1 is best known as the founding member of the E2F transcription factor family, which (together with retinoblastoma family proteins) regulates the expression of a large number of genes involved in DNA synthesis, cell cycle progression, DNA repair and apoptosis.^1,2 E2F1 has also been implicated in responses to DNA damage, and E2F1 is posttranslationally modified and stabilized in response to DNA damage and recruited to DNA strand breaks (DSBs). Previous studies have shown that E2F1 promotes nucleotide excision repair of UV-induced DNA damage, contributing to enhanced cell survival post-exposure.^3,4 A recent report by Chen et al. provides mechanistic teeth to previous associations between E2F1 and responses to DSBs by demonstrating a critical and direct role for E2F1 in the recruitment of repair factors to DSBs and subsequent repair, apparently independent of E2F1 roles in transcriptional regulation.⁵ Mutation or knockdown of E2F1, in both mouse and human cells, is shown to substantially reduce NBS1 phosphorylation, Rad51 accumulation and the formation of DNA damage foci containing Rad51, NBS1 and RPA. Importantly, the repair of DSBs is substantially delayed and reduced in cells with reduced E2F1. The formation of γH2AX foci is actually enhanced, because the resolution of the foci is delayed in E2F1-deficient cells following DNA damage. Thus, E2F1 appears to be required for the repair but not the recognition of DSBs.⁵ It remains to be determined how E2F1 mediates the recruitment of repair factors to DSBs, and the authors speculate that E2F1-dependent chromatin remodeling could contribute to effective repair.

Thus, in addition to its ability to promote apoptosis in response to DNA damage, E2F1 can also mediate DNA repair, which should promote clonogenic survival (Fig. 1). Whether by promoting the repair or the elimination of cells with DNA damage, E2F1 should contribute to the maintenance of genomic integrity, limiting the propagation of cells with potential DNA mutations. It will be important to better understand how E2F1 contributes to the cellular decision to repair or die following DNA damage and what role E2F1 plays in tissue maintenance and carcinogenesis following genotoxic insults. In some ways, this role for E2F1 is reminiscent of p53’s divergent cell fate impacts following DNA damage, where it can either play a pro-survival role, by instituting a temporary cell cycle arrest to allow for repair, or pro-death/senescence roles, preventing the clonogenic maintenance of the cells.⁶ In addition, p53 may also play a direct role in the repair of DNA strand breaks, independent of its role in regulating transcription.⁷ Given the known relationship between E2F1 and p53, it will be interesting to tease out how the interplay between these factors can control cell fate decisions, contributing to the “greater good” of the tissue: repair and retain or eliminate from the replicative cell pool.

Figure 1. E2F1 can either promote either DNA repair or apoptosis in response to DNA damage, which should exert opposing effects on cell survival.