Coupling mRNA synthesis and decay

Abstract

What has been will be again, what has been done will be done again; there is nothing new under the sun. -Ecclesiastes 1:9 (New International Version) Posttranscriptional regulation of gene expression has an important role in defining the phenotypic characteristics of an organism. Well-defined steps in mRNA metabolism that occur in the nucleus-capping, splicing, and polyadenylation-are mechanistically linked to the process of transcription. Recent evidence suggests another link between RNA polymerase II (Pol II) and a posttranscriptional process that occurs in the cytoplasm-mRNA decay. This conclusion appears to represent a conundrum. How could mRNA synthesis in the nucleus and mRNA decay in the cytoplasm be mechanistically linked? After a brief overview of mRNA processing, we will review the recent evidence for transcription-coupled mRNA decay and the possible involvement of Snf1, the Saccharomyces cerevisiae ortholog of AMP-activated protein kinase, in this process.

FIG 1

Cotranscriptional RNA processing in the nucleus. The capping enzymes are recruited once Pol II is phosphorylated at serine 5 in the carboxyl-terminal domain (CTD) during early elongation. The capping enzymes consist of RNA triphosphatase (RT), guanylyltransferase (GT), and 7-methyltransferase (MT) activities. As Pol II switches to productive elongation, the serine 5 phosphorylation disappears and serine 2 phosphorylation becomes dominant. The elongating Pol II complex recruits splicing enzymes, and the spliceosome removes the introns while transcription proceeds. The serine 2-phosphorylated CTD recruits the polyadenylation factors, including the RNA cleavage components and the poly(A) polymerase (PAP) to cleave the mRNA following the polyadenylation signal(s) (AAUAA) and add the poly(A) tail.

FIG 2

mRNA decay pathways in the cytoplasm. There are two major cytoplasmic pathways to degrade mRNA that both start with the shortening of the poly(A) tail by one of the deadenylase complexes (Ccr4-Not or Pan2/3). The exosome can degrade the deadenylated mRNA in the 3′-to-5′ direction, and the scavenger decapping enzyme, Dcs1, degrades the remaining cap. The most prominent pathway involves decapping by Dcp1 and Dcp2 and subsequent degradation by the 5′-to-3′ exonuclease, Xrn1.

FIG 3

Circular regulation of transcription and mRNA decay. (A) The first model, the model of Haimovich et al. (71), links transcription and decay together by the mRNA decay factors (DF) that shuttle between the cytoplasm and nucleus to regulate both processes. (B) The second model, the model of Sun et al. (72), shows that increased synthesis rates (SR) lead to increased levels of XRN1 mRNA, resulting in an increase in decay rates (DR). Increased levels of Xrn1 protein promote the higher synthesis rates inhibiting the induction of a global transcription repressor (Nrg1?). (C) The third model, the model of Braun et al. (94), shows Snf1 activating Xrn1, which leads to transcription of glucose-repressed genes and stabilization of the mRNA and subsequent glucose-induced decay.

FIG 4

mRNA-associated pathways targeted by Snf1. The black shapes represent Snf1 targets identified in a phosphoproteomic study (94). UAS, upstream activating sequence; ADA, Ada2/Gcn5/Ada3 transcription activator complex; SAGA, Spt-Ada-Gcn5-acetyltransferase; SLIK, SAGA-like complex; mRNP, messenger ribonucleoprotein particle.