Feedback to the central dogma: cytoplasmic mRNA decay and transcription are interdependent processes

Abstract

Transcription and RNA decay are key determinants of gene expression; these processes are typically considered as the uncoupled beginning and end of the messenger RNA (mRNA) lifecycle. Here we describe the growing number of studies demonstrating interplay between these spatially disparate processes in eukaryotes. Specifically, cells can maintain mRNA levels by buffering against changes in mRNA stability or transcription, and can also respond to virally induced accelerated decay by reducing RNA polymerase II gene expression. In addition to these global responses, there is also evidence that mRNAs containing a premature stop codon can cause transcriptional upregulation of homologous genes in a targeted fashion. In each of these systems, RNA binding proteins (RBPs), particularly those involved in mRNA degradation, are critical for cytoplasmic to nuclear communication. Although their specific mechanistic contributions are yet to be fully elucidated, differential trafficking of RBPs between subcellular compartments are likely to play a central role in regulating this gene expression feedback pathway.

Keywords: NITC; Xrn1; genetic buffering; host shutoff; mRNA decay; transcription.

Figure 1.

The homeostatic model of mRNA decay-transcription feedback proposes that appropriate mRNA levels are maintained by either altering mRNA decay or Pol II transcription. Removal of basal RNA decay factors results in decreased mRNA decay and stabilization of mRNAs; transcription then decreases to buffer against resulting increases in mRNA levels. Similarly, perturbations that cause reductions in transcription and thus less mRNA production are buffered through stabilization of mRNA.

Figure 2.

Cellular responses to mRNA destabilization include nonsense-induced transcriptional compensation (NITC) and decreased overall Pol II occupancy. mRNA with premature termination codons (PTCs) that are destabilized through the nonsense mediated decay pathway can recruit Upf proteins and members of the COMPASS complex. Upon translocation to the nucleus, they promote increased transcription of homologous genes by altering chromatin accessibility. Viral nucleases induce widespread mRNA decay by decapping or endonucleolytically cleaving mRNAs. Degradation of the resulting fragments by host exonucleases liberates previously bound RBPs, which are hypothesized to traffic into the nucleus in an mRNA concentration-dependent manner and decrease Pol II promoter occupancy.

Figure 3.

mRNA stability and Pol II transcription are linked processes, but may be differentially controlled during homeostasis or upon cellular threats. To maintain homeostatic mRNA levels and buffer against global mRNA abundance changes, eukaryotic cells modulate Pol II transcription or mRNA stability in a compensatory manner. However, during infection with mRNA decay-inducing viruses, the loss of mRNA is exacerbated by reduced Pol II transcription, perhaps as a component of a stress or antiviral response.

Figure 4.

Multiple models have been proposed to explain how Xrn1 connects mRNA stability with transcription. Xrn1 may act directly by shuttling into the nucleus to bind chromatin and reduce transcription. It may alternatively (or additionally) indirectly impact transcription by degrading transcripts encoding transcriptional regulators such as Nrg1, or by causing release of RNA binding proteins (RBPs) during accelerated mRNA decay, which traffic into the nucleus and result in reduced transcription.

Figure 5.

mRNA coordinators Rpb4/7 are implicated in imprinting mRNAs in the nucleus to convey transcription rate to the cytoplasm. Rpb4/7 have been shown to interact with the nascent mRNA chain in the nucleus and Pat1 and members of the Lsm1–7 complex in the cytoplasm. RNA decay factors Ccr4-Not and Xrn1 degrade mRNA in the cytoplasm and may affect Pol II elongation by either coordinating with (Ccr4-Not) or antagonizing (Xrn1) the Pol II co-factor TFIIS, which is responsible for disengaging stalled Pol II.