Quality Control of mRNA Function

be coupled to each other as well, a feat also thought to Most eukaryotic cellular proteins are generated by transbe orchestrated by the CTD as an additional measure lation of mRNAs that have successfully passed a number of QC. Efficient capping enhances both splicing and 39 of steps to insure their quality. Transcripts that fail to end formation, and efficient 39 end formation enhances pass selection are degraded or otherwise prevented splicing (Hirose and Manley, 2000, and Proudfoot, 2000, from engaging in protein synthesis. Recent studies have and references therein). Recent studies of Saccharobegun to elucidate the molecular mechanisms responsimyces cerevisiae have uncovered a nuclear discard ble for the preand cotranslational quality control (QC) of pathway for inefficiently spliced pre-mRNAs that apmRNA and the consequence to organisms when control pears to function in competition with the splicing pathfails. mRNA QC reflects physical interactions between way (Bousquet-Antonelli et al., 2000). Transcripts are components of the gene transcription, pre-mRNA prodegraded primarily in a 39 to 59 direction by the exosome, cessing, mRNA transport, and mRNA translation mabut can also be degraded 59 to 39 by Rat1p. Both the chineries. These interactions insure against transcript exosome and Rat1p have orthologs in mammals, sugdegradation when interactions are timely and proper, gesting that similar modes of degradation exist in higher but elicit nuclear retention of the transcript, or degradaeukaryotes. In light of recent data demonstrating that tion in the nucleus or cytoplasm, when interactions are transcription termination requires a poly(A) signal but delayed or abnormal. not transcript cleavage (Hirose and Manley, 2000, and Gene Transcription, and Pre-mRNA Synthesis Proudfoot, 2000, and references therein), it is conceivand Processing able that this discard pathway also eliminates tranmRNA QC begins at the level of gene transcription. The scripts that undergo inefficient 39 end formation. cotranscriptional nature of pre-mRNA processing offers mRNA Export a number of opportunities for transcription to affect the After pre-mRNA processing, product mRNAs are exquality and quantity of mRNA. Evidence that the transcripported to the cytoplasm. Export offers yet another tional machinery can regulate pre-mRNA processing deform of mRNA QC because it is a selective and active rives in part from the finding that sequence changes in process that discriminates between immature and mathe human fibronectin promoter can alter splice site ture mRNP. mRNA export is attributable to bound proselection, possibly through the differential recruitment teins that promote export, many of which are acquired of splicing factors, in this case SR proteins SF2/ASF as a consequence of pre-mRNA processing, and can and 9G8, to the CTD, the carboxyl terminal domain of be inhibited by bound proteins that block export, some the largest subunit of RNA polymerase II (Cramer et al., of which are the consequence of incomplete pre-mRNA 1999). As additional evidence, the transcription factor