AI Article Synopsis
- Tight regulation of mRNA isoform expression is key for neuronal development and function, but the proteins that control this process are not fully understood.
- Researchers discovered that the RNA kinase CLP1 influences mRNA isoform expression by affecting how cleavage and polyadenylation (important steps in mRNA processing) occur.
- In studies, motor neurons lacking CLP1 exhibited altered patterns in mRNA processing that led to reduced diversity in mRNA isoforms, a finding echoed in brain tissue samples from patients with neurodegenerative diseases, suggesting a potential common mechanism in these conditions.
Article Abstract
Tight regulation of mRNA isoform expression is essential for neuronal development, maintenance, and function; however, the repertoire of proteins that govern isoform composition and abundance remains incomplete. Here, we show that the RNA kinase CLP1 regulates mRNA isoform expression through suppression of proximal cleavage and polyadenylation. We found that human stem-cell-derived motor neurons without CLP1 or with the disease-associated CLP1 p.R140H variant had distinct patterns of RNA-polymerase-II-associated cleavage and polyadenylation complex proteins that correlated with polyadenylation site usage. These changes resulted in imbalanced mRNA isoform expression of long genes important for neuronal function that were recapitulated in vivo. Strikingly, we observed the same pattern of reduced mRNA isoform diversity in 3' end sequencing data from brain tissues of patients with neurodegenerative disease. Together, our results identify a previously uncharacterized role for CLP1 in mRNA 3' end formation and reveal an mRNA misprocessing signature in neurodegeneration that may suggest a common mechanism of disease.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9035109 | PMC |
| http://dx.doi.org/10.1016/j.neuron.2022.01.018 | DOI Listing |
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