The retinoblastoma protein (Rb) was the first cloned tumor suppressor gene, and its study established the paradigm for how loss of cell cycle control contributes to tumorigenesis. One long-standing question is why is Rb a more potent tumor suppressor than its close Rb-like homologs p107 and p130. Here, we addressed this question by identifying differences in Rb and p107 structure and the source of their preferences in binding different E2F transcription factor family members. We combined these insights with comparative genomics to show that Rb evolved structural features that confer a unique ability to bind those E2Fs that most potently activate cell division. This protein-protein evolution occurred at the base of jawed vertebrates after their divergence from Agnatha (jawless fish). This was a fun cell cycle collaboration between the Rubin (biochemists) and Buchler labs (genomicists).
Liban TJ, Medina EM, Tripathi S, Sengupta S, Henry RW, Buchler NE, Rubin SM. Conservation and divergence of C-terminal domain structure in the retinoblastoma protein family. Proc. Natl. Acad. Sci. USA 114: 4942 (2017)
Although cell cycle control is an ancient, conserved, and essential process, some core animal and fungal cell cycle regulators share no more sequence identity than non-homologous proteins. Edgar Medina used a phylogenomic approach to show that evolution along the fungal lineage was punctuated by the early acquisition and entrainment of SBF transcription factor through horizontal gene transfer. Cell cycle evolution in the fungal ancestor then proceeded through a hybrid network containing both SBF and its ancestral animal counterpart E2F, which is still maintained in many basal fungi (e.g. Spizellomyces punctatus, shown in picture). We hypothesized that a virally-derived SBF may have initially hijacked cell cycle control by activating transcription via the cis-regulatory elements targeted by the ancestral cell cycle regulator E2F, much like extant viral oncogenes. Consistent with this hypothesis, our data show that SBF can regulate promoters with E2F binding sites in budding yeast. This was a fun and fruitful collaboration with the Skotheim and Gordan labs. You can read more about this research (“Hijacked cell division helped fuel rise of Fungi” by Robin A. Smith) at Duke Today.
Medina EM, Turner JJ, Gordan R, Skotheim JM, Buchler NE. Punctuated evolution and transitional hybrid network in an ancestral cell cycle of fungi. eLife 5:e09492 (2016)
Physarum polycephalum (“many-headed slime”) is a giant amoeba with similarities to the common ancestor of amoeba, fungi and animals. Our lab helped analyze its genome to show that it has molecular features that were once thought to be specific for either animals or plants. Like animals (but unlike plants or fungi), Physarum uses tyrosine-kinase signaling for processing. Nick Buchler analyzed cell cycle regulators in Physarum and other amoeboid genomes to show that Physarum may be a better model organism than yeast and fungi for studying conserved mechanisms of cell cycle regulation in the ancestor of amoeba and animals.
Schaap P et al, The Physarum polycephalum genome reveals extensive use of prokaryotic two-component and metazoan-type tyrosine kinase signaling. Genome Biol Evol. 8: 109 (2016)