Post-transcriptional RNA regulons affecting cell cycle and proliferation

Abstract

The cellular growth cycle is initiated and maintained by punctual, yet agile, regulatory events involving modifications of cell cycle proteins as well as coordinated gene expression to support cyclic checkpoint decisions. Recent evidence indicates that post-transcriptional partitioning of messenger RNA subsets by RNA-binding proteins help physically localize, temporally coordinate, and efficiently translate cell cycle proteins. This dynamic organization of mRNAs encoding cell cycle components contributes to the overall economy of the cell cycle consistent with the post-transcriptional RNA regulon model of gene expression. This review examines several recent studies demonstrating the coordination of mRNA subsets encoding cell cycle proteins during nuclear export and subsequent coupling to protein synthesis, and discusses evidence for mRNA coordination of p53 targets and the DNA damage response pathway. We consider how these observations may connect to upstream and downstream post-transcriptional coordination and coupling of splicing, export, localization, and translation. Published examples from yeast, nematode, insect, and mammalian systems are discussed, and we consider genetic evidence supporting the conclusion that dysregulation of RNA regulons may promote pathogenic states of growth such as carcinogenesis.

Keywords: Cancer; DNA damage; Posttranscriptional regulation; RNA-binding proteins; Translational control; p53.

Figure 1. Depictions of RNA regulon models

A. Coordinated mRNA export showing two yeast RBP export factors Mex67 and Yra1 as they transport groups of functionally related mRNAs out of the nucleus from derived from the data of Hieronymus and Silver (2003) [50]. Adapted with permission from Keene, Nature Genetics 33: 111–112 (2003) [51]. B. Coordinated regulation of the yeast PUF3 RBP transporting nuclear mRNAs that encode mitochondrial proteins to mitochondria for translation and uptake from Gerber et al., (2004) [34]. Adapted with permission from Keene, Nature Reviews Genetics 8:533–543 (2007) [3].

Figure 2. Coupling of RNA Regulons

A model of two distinct RNA processing pathways are depicted for a set of mRNAs. The functionally related set of mRNAs in blue are spliced, exported and translated through regulatory events directed by splicing factor A, export factor B and translation factor C in RNA regulons that are coupled together through interactions between A, B and C. The functionally related set of mRNAs in red are likewise spliced, exported and translated by D, E and F, respectively, through similar coupling.

Figure 3. Cell cycle regulation by RBPs

Several RBPs have been genetically demonstrated to influence cell cycle events, including export factor NUP98 and translation factors PUM1, DND1 and GLD-1 as described in the text. Interestingly, these all act as repressors of cell growth, and therefore, have been characterized as tumor suppressors. Loss of function of these RBPs causes increased cell growth through failures of various cell cycle checkpoints.