Key Points
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Studies of pRB and E2F function in flies and worms share some important similarities that provide insight into the core activities of these proteins and show how a common regulatory module can control various biological functions in different organisms.
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In Drosophila melanogaster, RBF and dE2F proteins are key regulators of cell proliferation. E2F-protein control results from the functional interplay between activator and repressor complexes. dE2F and RBF proteins have also been linked to the control of re-replication and function in the cellular responses to DNA damage.
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Mutation of the Caenorhabditis elegans pRB and E2F genes cause developmental defects with limited changes in cell proliferation. C. elegans pRB and E2F complexes repress the expression of developmentally controlled genes and have an important role in maintaining distinct patterns of gene expression in the germline and soma.
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Genetic studies in C. elegans place pRB and E2F into a large set of genes with a shared function in the formation of the vulva (synMuv B genes).
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Despite the apparently different uses of pRB and E2F proteins in flies and worms, these proteins share a common molecular mechanism of action that is also preserved in mammalian cells. In each species, pRB and E2F proteins form stable complexes (dREAM/MMB complexes) with orthologues of synMuv B genes.
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dREAM/MMB complexes function as molecular switches and provide patterns of gene repression that are stable, but also readily reversible. These complexes probably affect some aspect of chromatin structure, but precisely how the switch works is not yet known.
Abstract
Proteins that are related to the retinoblastoma tumour suppressor pRB and the E2F transcription factor are conserved in many species of plants and animals. The mammalian orthologues of pRB and E2F are best known for their roles in cell proliferation, but it has become clear that they affect many biological processes. Here we describe the functions of pRB-related proteins and E2F proteins that have emerged from genetic and biochemical experiments in Caenorhabditis elegans and Drosophila melanogaster. The similarities that have been observed between worms, flies and mammals provide insight into the core activities of pRB and E2F proteins and show how a common regulatory module can control various biological functions in different organisms.
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Acknowledgements
We thank D. Fay, B. Duronio, M. Frolov and members of our laboratories for their comments and I. The for help with the figures. Because of the length restrictions we were unable to cover several important topics and we apologize to colleagues for studies that could not be described in full detail. The research in our laboratories was funded by grants from the National Institutes of Health.
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Glossary
- Mosaic animal
-
An animal with genetically distinct populations of cells that arose from a single zygote.
- Polycomb group
-
(PcG).Proteins that form several multiprotein complexes that mediate stable repression of gene expression over multiple cell generations, in association with histone H3 Lys27 methylation.
- Wing imaginal disc
-
A sheet of cells that are the precursors to the adult wing.
- Wing margin
-
The outer edge of the adult wing.
- Endoreduplication
-
Repeated rounds of DNA synthesis without ensuing mitosis and cell division.
- DEAD-box protein
-
A member of a family of proteins that are characterized by the presence of nine conserved sequence motifs. Several members of this family are RNA helicases with ATPase activity.
- RbAp48
-
(pRB-associated protein p48). A subunit of multiple histone modification complexes and chromatin-remodelling complexes that can interact with histones H3 and H4.
- Histone deacytylase
-
A class of enzymes that remove the acetyl groups of Lys residues on histones. The HDAC1/RPD3 family form part of multisubunit nuclear complexes with key roles in eukaryotic gene expression.
- SET domain
-
A domain that is present in proteins that transfer methyl groups to substrate Lys residues, found in nearly all histone Lys methyltransferases (HMTs).
- Eye imaginal disc
-
A sheet of cells that are the precursors to the adult eye.
- Chorion gene clusters
-
Genome regions that are amplified in follicle cells and contain genes that are needed for the formation of the eggshell.
- NuRD
-
Nucleosome remodeling and deacytylase complex. A complex that combines histone deacetylation and chromatin remodelling ATPase activities.
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van den Heuvel, S., Dyson, N. Conserved functions of the pRB and E2F families. Nat Rev Mol Cell Biol 9, 713–724 (2008). https://doi.org/10.1038/nrm2469
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DOI: https://doi.org/10.1038/nrm2469
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