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)