About this Research Topic
One of the most ancient of regulatory molecules, retinoblastoma (Rb) proteins are evolutionarily conserved transcriptional corepressors and chromatin regulators found in most eukaryotes, from algae and plants to animals. Over the course of evolution, the genes encoding Rb proteins have diversified in many lineages, along with their DNA binding partners, the E2F and DP-family transcription factors. The original studies of their function came from eponymous retinoblastoma cancers, a childhood condition that can originate from germline or somatic mutations. Pioneering studies by Alfred Knudsen were the first to infer that loss of this recessive gene led to tumor formation, and it was through these genetic studies that the concept of tumor suppressor genes originated. Rb is known to be mutated or inactivated in a host of human cancers, thus studies of Rb and its vertebrate paralogs, p107 and p130, have focused on a conserved role in regulation of cell cycle genes. Consistent with this activity, cyclin-dependent kinases plays an important and conserved role in phosphorylation of Rb-related proteins.
In addition to cell cycle control, genetic studies in model organisms have pointed to widespread roles for Rb and paralogs in development and metabolic regulation. Genome-wide studies have furthermore indicated that Rb-related proteins can be associated with distinct regulatory complexes that have different functional outputs for associated genes; in fact, some Rb complexes evade canonical cell cycle signals to deliver unique developmentally-controlled regulation. Rb proteins have also been found to physically associate and influence the expression of housekeeping genes through a phenomenon termed “soft repression”, which contrasts with the typical on/off output associated with canonical cell-cycle genes.
Rb protein family members are characterized by conserved central “pocket” domains, whose functions include interactions with E2F/DP transcription factors as well as interactions with chromatin remodeling proteins important for transcriptional regulation. More diverged N- and C-terminal regions provide paralog-specific binding specificity as well as interaction surfaces for cyclins. Comparative studies have highlighted deep conservation for roles in control of the cell cycle; however there is less understanding of the functional impact of Rb gene duplications – do these events, which have originated in multiple lineages, including vertebrates and flies, represent subfunctionalization, neofunctionalization, or a combination of these processes? In addition, given the partially overlapping occupancy of Rb paralogs at many genes, are their molecular activities redundant, or does each paralog have novel activities?
Some clues to about Rb-related protein functional diversification have come from diverse lineages; for instance, the cell-cycle role of Rb in Chlamydomonas is not associated with loss of promoter binding, unlike the case in other systems. The p107 paralog in mammals has a novel E2F-binding surface in the C-terminus that allows it to differentiate between E2F family members. In the fly, the more derived Rbf2 paralog lacks a conserved block of C-terminal residues, and shows a greatly expanded in vivo targeting preference. Rb evolution has also been suggested to underlie the development of multicellularity and sexually dimorphic development in volvocine green algae.
Major questions remain to be answered concerning this central family of transcriptional regulators; in the realm of human health, the assumption that Rb paralogs p107 and p130 are “partially redundant” and hence of lesser importance should be reexamined. Similarly, the apparent dispensability of the conserved Drosophila Rbf2 gene suggests a cryptic or undiscovered function that is maintained under selection. Regarding identification of transcriptional control pathways, the pleiotropic phenotypes evoked by disruption of cell-cycle related functions through Rb mutations may mask other pervasive but subtle regulatory effects, including “soft repression”.
Finally, a number of chromatin-based molecular mechanisms of repression have been suggested for Rb-related proteins, but potential promoter-specific effects are poorly understood. The diversity of Rb paralogs provides an opportunity to leverage natural experiments to better understand at a mechanistic and evolutionary level the action of Rb proteins.
Papers suitable for this topic will include:
• Genetics of RB proteins in diverse systems, including redundancy or specialization
• Genomic and bioinformatic analysis of RB family proteins
• RB connections to evolution and development
• Mechanisms of RB family proteins
• Comparative structural analysis of RB paralogs, including primary and tertiary structure
• Metabolic pathways regulated by RB and its paralogs
Keywords: Retinoblastoma, p107, p130, lin-35, Rbf1, Rbf2, Mat3, RBR1, DREAM, cell-cycle, tumor suppressor, evolution, transcription
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