The Retinoblastoma proteins are a family of transcriptional co-repressors that play important roles in regulating various cellular processes, including cell proliferation, differentiation and apoptosis. There are three retinoblastoma family proteins in humans; Rb, p107 and p130, which perform overlapping yet distinct roles in regulating the transcription of genes involved in diverse processes. The molecular mechanisms underlying the distinct functions of the retinoblastoma proteins are not fully understood, but may include differences in complex formation with E2f factors as well as interactions with distinct chromatin modifying and remodeling factors. Gene duplication is rare in the retinoblastoma gene family; most metazoan genomes encode a single retinoblastoma protein. Interestingly, Drosophila has undergone an independent duplication event that yielded an ancestral Rbf1 gene and a more derived Rbf2 gene, which makes it a good system to study paralogy in this family. Structurally, Rbf1 resembles p107 and p130 most closely, and bears a conserved regulatory C-terminal domain (IE) that is critical for stability and activity of these proteins. The IE is lost in Rb and Rbf2, which are the more derived forms of the protein, suggesting that the presence or absence of the IE may contribute to the different functions of these proteins. Here, using genomic approaches, I provide new insights on the function of Rbf2, which were not apparent from prior cell-based assays. I show that Rbf2 regulates a set of cell growth related genes, and has an impact on fertility and lifespan of flies. I define cis regulatory features of CycB gene that allow preferential repression by Rbf2, indicating that it is not merely a weaker version of Rbf1 as previously thought, but a highly effective repressor in certain contexts. I furthermore show using transcriptomic studies that the IE of Rbf1 is critical for the repression function of this protein in a gene specific manner. Mutation of specific conserved residues within the IE have a distinct impacts on subsets of genes, indicating that the IE is an important regulatory element for specific sets of genes. The specialization of retinoblastoma function in Drosophila may reflect a parallel evolution found in vertebrates, and raises the possibility that control of cell growth control is equally important to cell cycle function for this conserved family of transcriptional corepressors.
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