The Long and Short of MicroRNA Yates, Luke A.; Norbury, Chris J.; Gilbert, Robert J.C.
Cell,
04/2013, Volume:
153, Issue:
3
Journal Article
Peer reviewed
Open access
MicroRNAs (miRNAs) are versatile regulators of gene expression in higher eukaryotes. In order to silence many different mRNAs in a precise manner, miRNA stability and efficacy is controlled by highly ...developed regulatory pathways and fine-tuning mechanisms both affecting miRNA processing and altering mature miRNA target specificity.
The addition of poly(A) tails to eukaryotic nuclear mRNAs promotes their stability, export to the cytoplasm and translation. Subsequently, the balance between exonucleolytic deadenylation and ...selective re-establishment of translation-competent poly(A) tails by cytoplasmic poly(A) polymerases is essential for the appropriate regulation of gene expression from oocytes to neurons. In recent years, surprising roles for cytoplasmic poly(A) polymerase-related enzymes that add uridylyl, rather than adenylyl, residues to RNA 3' ends have also emerged. These terminal uridylyl transferases promote the turnover of certain mRNAs but also modify microRNAs, their precursors and other small RNAs to modulate their stability or biological functions.
Shortly before the DNA era began, PC Koller described lagging chromosomes and chromosome numerical abnormalities in human carcinomas. While present-day cancer geneticists would question some of ...Koller's conclusions, this study ultimately contributed to the realisation that chromosomal instability is a widespread feature of solid tumours.
Most mammalian protein coding genes are subject to alternative cleavage and polyadenylation (APA), which can generate distinct mRNA 3'UTRs with differing regulatory potential. Although this process ...has been intensely studied in recent years, it remains unclear how and to what extent cleavage site selection is regulated under different physiological conditions. The cleavage factor Im (CFIm) complex is a core component of the mammalian cleavage machinery, and the observation that its depletion causes transcriptome-wide changes in cleavage site use makes it a key candidate regulator of APA. This review aims to summarize current knowledge of the CFIm complex, and explores the evidence surrounding its potential contribution to regulation of APA.
Both end structures of eukaryotic mRNAs, namely the 5' cap and 3' poly(A) tail, are necessary for transcript stability, and loss of either is sufficient to stimulate decay. mRNA turnover is ...classically thought to be initiated by deadenylation, as has been particularly well described in Saccharomyces cerevisiae. Here we describe two additional, parallel decay pathways in the fission yeast Schizosaccharomyces pombe. First, in fission yeast mRNA decapping is frequently independent of deadenylation. Second, Cid1-dependent uridylation of polyadenylated mRNAs, such as act1, hcn1 and urg1, seems to stimulate decapping as part of a novel mRNA turnover pathway. Accordingly, urg1 mRNA is stabilized in cid1Delta cells. Uridylation and deadenylation act redundantly to stimulate decapping, and our data suggest that uridylation-dependent decapping is mediated by the Lsm1-7 complex. As human cells contain Cid1 orthologs, uridylation may form the basis of a widespread, conserved mechanism of mRNA decay.
DNA damage-induced apoptosis Norbury, Chris J; Zhivotovsky, Boris
Oncogene,
04/2004, Volume:
23, Issue:
16
Journal Article
Peer reviewed
Open access
Unicellular organisms respond to the presence of DNA lesions by activating cell cycle checkpoint and repair mechanisms, while multicellular animals have acquired the further option of eliminating ...damaged cells by triggering apoptosis. Defects in DNA damage-induced apoptosis contribute to tumorigenesis and to the resistance of cancer cells to a variety of therapeutic agents. The intranuclear mechanisms that signal apoptosis after DNA damage overlap with those that initiate cell cycle arrest and DNA repair, and the early events in these pathways are highly conserved. In addition, multiple independent routes have recently been traced by which nuclear DNA damage can be signalled to the mitochondria, tipping the balance in favour of cell death rather than repair and survival. Here, we review current knowledge of nuclear DNA damage signalling, giving particular attention to interactions between these nuclear events and apoptotic processes in other intracellular compartments.
Inhibition of eukaryotic DNA replication leads to the rapid suppression of histone synthesis, via 3' uridylation of cytoplasmic histone mRNAs followed by their Lsm1-7-mediated decapping and ...degradation. Here we show that the human cytoplasmic RNA terminal U-transferase ZCCHC11, recently implicated in microRNA metabolism, associates with replication-dependent histone mRNAs. Knockdown of ZCCHC11 selectively blocked histone mRNA degradation following inhibition of DNA replication, whereas knockdown of PAPD1 or PAPD5, previously proposed as candidate histone mRNA U-transferases, had no such effect. Furthermore, a reduction in the proportion of histone transcripts that were uridylated was observed following ZCCHC11 knockdown. Our data indicate that ZCCHC11 is the terminal U-transferase responsible for targeting human histone mRNAs for degradation following inhibition or completion of DNA replication.
Managing vertebrate pests is a global conservation challenge given their undesirable socio-ecological impacts. Pest management often focuses on the ‘average’ individual, neglecting individual-level ...behavioural variation (‘personalities’) and differences in life histories. These differences affect pest impacts and modify attraction to, or avoidance of, sensory cues. Strategies targeting the average individual may fail to mitigate damage by ‘rogues’ (individuals causing disproportionate impact) or to target ‘recalcitrants’ (individuals avoiding standard control measures). Effective management leverages animal behaviours that relate primarily to four core motivations: feeding, fleeing, fighting, and fornication. Management success could be greatly increased by identifying and exploiting individual variation in motivations. We provide explicit suggestions for cue-based tools to manipulate these four motivators, thereby improving pest management outcomes.
The explicit consideration of individual traits is central to enhancing effective vertebrate pest management.We provide a heuristic framework for understanding animal motivations and cues across spatial scales.Focussing on individual motivations can improve population-level control measures and reduce the impacts of problematic individuals that cause the most damage.Incorporating principles of behavioural ecology will increase the effectiveness of any intervention while providing an opportunity to test behavioural theory in a natural context.
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