Activation and inhibition of nonsense-mediated mRNA decay control the abundance of alternative polyadenylation products.

Alternative polyadenylation (APA) produces transcript 3' untranslated regions (3'UTRs) with distinct sequences, lengths, stabilities and functions. We show here that APA products include a class of cryptic nonsense-mediated mRNA decay (NMD) substrates with extended 3'UTRs that gene- or transcript-level analyses of NMD often fail to detect. Transcriptome-wide, the core NMD factor UPF1 preferentially recognizes long 3'UTR products of APA, leading to their systematic downregulation.

hnRNP L-dependent protection of normal mRNAs from NMD subverts quality control in B cell lymphoma.

The human nonsense-mediated mRNA decay pathway (NMD) performs quality control and regulatory functions within complex post-transcriptional regulatory networks. In addition to degradation-promoting factors, efficient and accurate detection of NMD substrates involves proteins that safeguard normal mRNAs. Here, we identify hnRNP L as a factor that protects mRNAs with NMD-inducing features including long 3'UTRs.

Estimating lead-time bias in lung cancer diagnosis of patients with previous cancers.

Surprisingly, survival from a diagnosis of lung cancer has been found to be longer for those who experienced a previous cancer than for those with no previous cancer. A possible explanation is lead-time bias, which, by advancing the time of diagnosis, apparently extends survival among those with a previous cancer even when they enjoy no real clinical advantage. We propose a discrete parametric model to jointly describe survival in a no-previous-cancer group (where, by definition, lead-time bias cannot exist) and in a previous-cancer group (where lead-time bias is possible).

Novobiocin binding to NalD induces the expression of the MexAB-OprM pump in Pseudomonas aeruginosa.

NalD was reported to be the secondary repressor of the MexAB-OprM multidrug efflux pump, the major system contributing to intrinsic multidrug resistance in Pseudomonas aeruginosa. Here, we show that novobiocin binds directly to NalD, which leads NalD to dissociate from the DNA promoter, and thus de-represses the expression of the MexAB-OprM pump. In addition, we have solved the crystal structure of NalD at a resolution of 2.

Polypyrimidine tract binding protein 1 protects mRNAs from recognition by the nonsense-mediated mRNA decay pathway.

The nonsense-mediated mRNA decay (NMD) pathway degrades mRNAs containing long 3'UTRs to perform dual roles in mRNA quality control and gene expression regulation. However, expansion of vertebrate 3'UTR functions has required a physical expansion of 3'UTR lengths, complicating the process of detecting nonsense mutations. We show that the polypyrimidine tract binding protein 1 (PTBP1) shields specific retroviral and cellular transcripts from NMD.

Real-time prediction of clinical trial enrollment and event counts: A review.

Clinical trial planning involves the specification of a projected duration of enrollment and follow-up needed to achieve the targeted study power. If pre-trial estimates of enrollment and event rates are inaccurate, projections can be faulty, leading potentially to inadequate power or other mis-allocation of resources. Recent years have witnessed the development of methods that use the accumulating data from the trial itself to create improved predictions in real time.

Non-stop mRNA decay initiates at the ribosome.

The translation machinery deciphers genetic information encoded within mRNAs to synthesize proteins needed for various cellular functions. Defective mRNAs that lack in-frame stop codons trigger non-productive stalling of ribosomes. We investigated how cells deal with such defective mRNAs, and present evidence to demonstrate that RNase R, a processive 3'-to-5' exoribonuclease, is recruited to stalled ribosomes for the specific task of degrading defective mRNAs.

Structural insight into the oxidation-sensing mechanism of the antibiotic resistance of regulator MexR.

MexR functions as the primary regulator of the mexAB-oprM multidrug efflux expression in Pseudomonas aeruginosa. It has been shown that MexR senses oxidative stress by interprotomer disulphide bond formation between redox-active cysteines. This oxidation induces MexR to dissociate from the promoter DNA, thus activating the transcriptional expression of efflux pump genes.

Co-evolution of multipartite interactions between an extended tmRNA tag and a robust Lon protease in Mycoplasma.

Messenger RNAs that lack in-frame stop codons promote ribosome stalling and accumulation of aberrant and potentially harmful polypeptides. The SmpB-tmRNA quality control system has evolved to solve problems associated with non-stop mRNAs, by rescuing stalled ribosomes and directing the addition of a peptide tag to the C-termini of the associated proteins, marking them for proteolysis. In Escherichia coli, the ClpXP system is the major contributor to disposal of tmRNA-tagged proteins.

Studying tmRNA-mediated surveillance and nonstop mRNA decay.

In bacteria, ribosomes stalled at the 3'-end of nonstop or defective mRNAs are rescued by the action of a specialized ribonucleoprotein complex composed of tmRNA and SmpB protein in a process known as trans-translation; for recent reviews see Dulebohn et al. [2007], Keiler [2007], and Moore and Sauer [2007]. tmRNA is a bifunctional RNA that acts as both a tRNA and an mRNA.