Biomedical subjects

Ken Dower

Publications and source records attributed to Ken Dower.

4 recordsLinked to original sources

PubMed2026

Unleashing innovative cross-organ fibrosis therapies by harnessing the omics revolution.

Fibrosis is a major cause of mortality and morbidity worldwide with limited therapeutic options. Our understanding of fibrosis has significantly improved and led to the identification of "core" fibrogenic mechanisms that fuel a self-sustaining vicious cycle following the initial insult. The fibrotic niche is the result of complex cellular and molecular interactions that need to be disrupted to achieve transformational therapies. In this Review, we describe the current understanding of fibrogenic mechanisms, the progress and limitations of omics approaches in the identification of novel fibrotic pathways, and advances in therapeutic modalities that all together have the potential to unleash innovative cross-organ antifibrotic therapies.

Humans↗

PubMed2003

Early formation of mRNP: license for export or quality control?

Eukaryotic mRNA is processed by enzymes and packaged with proteins within nuclei to generate functional messenger ribonucleoprotein (mRNP) particles. Processing and packaging factors can interact with mRNA cotranscriptionally to form an early mRNP. Erroneous mRNP formation leads to nuclear retention and degradation of the mRNA. It therefore appears that one function of cotranscriptional mRNP assembly is to discard aberrant mRNPs early in their biogenesis. Cotranscriptional mRNP assembly may also enable the transcription machinery to respond to improper mRNP formation.

Cell Nucleus↗

PubMed2002

T7 RNA polymerase-directed transcripts are processed in yeast and link 3' end formation to mRNA nuclear export.

We have characterized transcripts synthesized in vivo by bacteriophage T7 RNA polymerase to investigate yeast mRNA processing. T7 transcripts are not capped, consistent with capping being tightly coupled to RNA polymerase II (pol II) transcription. In contrast to higher eukaryotic non-pol II transcripts, yeast T7 transcripts are spliced as well as cleaved and polyadenylated. However, T7 and pol II transcripts are affected differently in cleavage and polyadenylation mutant strains, indicating that pol II may have a role in yeast 3' end formation. T7 transcripts with 3' ends directed by a polyadenylation signal are exported from the nucleus, and this export is dependent on the canonical cleavage and polyadenylation machinery. Importantly, transcripts with T7 terminator-directed 3' ends are unadenylated and predominantly nuclear in wild-type cells. Our results suggest that transcription by pol II is required for neither the nuclear export of an in vivo-transcribed mRNA nor for the retention of transcripts with aberrant 3' ends. Moreover, proper 3' end formation may be necessary and sufficient to promote mRNA export in yeast.

Active Transport, Cell Nucleus↗

PubMed2002

Interactions between mRNA export commitment, 3'-end quality control, and nuclear degradation.

Several aspects of eukaryotic mRNA processing are linked to transcription. In Saccharomyces cerevisiae, overexpression of the mRNA export factor Sub2p suppresses the growth defect of hpr1 null cells, yet the protein Hpr1p and the associated THO protein complex are implicated in transcriptional elongation. Indeed, we find that a pool of heat shock HSP104 transcripts are 3'-end truncated in THO complex mutant as well as sub2 mutant backgrounds. Surprisingly, however, this defect can be suppressed by deletion of the 3'-5' exonuclease Rrp6p. This indicates that incomplete RNAs result from nuclear degradation rather than from a failure to efficiently elongate transcription. RNAs that are not degraded are retained at the transcription site in a Rrp6p-dependent manner. Interestingly, the addition of a RRP6 deletion to sub2 or to THO complex mutants shows a strong synthetic growth phenotype, suggesting that the failure to retain and/or degrade defective mRNAs is deleterious. mRNAs produced in the 3'-end processing mutants rna14-3 and rna15-2, as well as an RNA harboring a 3' end generated by a self-cleaving hammerhead ribozyme, are also retained in Rrp6p-dependent transcription site foci. Taken together, our results show that several classes of defective RNPs are subject to a quality control step that impedes release from transcription site foci and suggest that suboptimal messenger ribonucleoprotein assembly leads to RNA degradation by Rrp6p.

Active Transport, Cell Nucleus↗