Direct Regulation of DNA Repair by E2F and RB in Mammals and Plants: Core Function or Convergent Evolution?

Abstract

Members of the E2F transcription factor family regulate the expression of genes important for DNA replication and mitotic cell division in most eukaryotes. Homologs of the retinoblastoma (RB) tumor suppressor inhibit the activity of E2F factors, thus controlling cell cycle progression. Organisms such as budding and fission yeast have lost genes encoding E2F and RB, but have gained genes encoding other proteins that take on E2F and RB cell cycle-related functions. In addition to regulating cell proliferation, E2F and RB homologs have non-canonical functions outside the mitotic cell cycle in a variety of eukaryotes. For example, in both mammals and plants, E2F and RB homologs localize to DNA double-strand breaks (DSBs) and directly promote repair by homologous recombination (HR). Here, we discuss the parallels between mammalian E2F1 and RB and their Arabidopsis homologs, E2FA and RB-related (RBR), with respect to their recruitment to sites of DNA damage and how they help recruit repair factors important for DNA end resection. We also explore the question of whether this role in DNA repair is a conserved ancient function of the E2F and RB homologs in the last eukaryotic common ancestor or whether this function evolved independently in mammals and plants.

Keywords: ATM; BRG1; E2F1; TopBP1; homologous recombination; p300/CBP.

Figure 1

Conservation of E2F and RB in the Last Common Eukaryotic Ancestor (LECA). (A) Structure of the three types of E2F family member proteins. (B) The cell cycle regulatory network of the LECA based on genomic sequence comparisons across eukaryotic groups.

Figure 2

Hijacking of the RB-E2F pathway by viral proteins in the fungal ancestor and in cervical cancers. (A) SBF transcription factors in fungi may have arisen through a horizontal gene transfer event involving a virus encoding a KilA-N-related protein. (B) Human papilloma virus (HPV) encodes the E7 oncoprotein, which inhibits RB and activates endogenous E2F transcription factors to drive expression of cellular genes needed for viral replication. E7 is one of the viral genes that is integrated into the genome of most cervical cancer cells.

Figure 3

E2F and RB homologs in mammals and plants localize to DNA double-strand breaks in an ATM-dependent manner to directly promote repair by homologous recombination. In mammals, E2F1 post-translational modifications regulate protein–protein interactions that localize E2F1-RB to double-strand breaks and recruit the chromatin modifying enzymes p300/CBP and BRG1. Whether E2F and RB homologs directly regulate DNA repair by similar mechanisms in other eukaryotes is unknown.

Figure 4

The E2F1 protein N-terminal motif phosphorylated by ATM and required for E2F1 and RB location to DNA damage is not conserved beyond placental mammals.