Alternative polyadenylation alters protein dosage by switching between intronic and 3'UTR sites

Authors: DE PRISCO, NICOLA - Columbia University Medical Center; FORD, CAITLIN - Columbia University Medical Center; ELROD, NATHAN - University Of Texas Medical Branch; LEE, WINSTON - Columbia University Medical Center; TANG, LAUREN - Columbia University - New York; HUANG, KAI-LIEH - University Of Texas Medical Branch; LIN, AI - Chinese Academy Of Medical Sciences; JI, PING - University Of Texas Medical Branch; JONNAKUTI, VENKATA - Baylor College Of Medicine; BOYLE, LIA - Columbia University Medical Center; CABAJ, MAXIMILIAN - Columbia University Medical Center; BOTTA, SALVATORE - Columbia University Medical Center; YALAMANCHILI, HARI - Children'S Nutrition Research Center (CNRC)

Submitted to: Science Advances
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 1/19/2023
Publication Date: 2/17/2023
Citation: De Prisco, N., Ford, C., Elrod, N.D., Lee, W., Tang, L.C., Huang, K., Lin, A., Ji, P., Jonnakuti, V.S., Boyle, L., Cabaj, M., Botta, S., Yalamanchili, H.K. 2023. Alternative polyadenylation alters protein dosage by switching between intronic and 3'UTR sites. Science Advances. 9(7). Article eade4814. https://doi.org/10.1126/sciadv.ade4814.
DOI: https://doi.org/10.1126/sciadv.ade4814

Interpretive Summary: Living cells carry out a host of complex processes to sustain life. Among these, a process known as polyadenylation stands out for its crucial role. This research dives into polyadenylation's intricate workings within our cells and how it enriches the variety of proteins our bodies generate. Polyadenylation, simply put, is like a tailor who can create different versions of a product from a single pattern. Here, the pattern is our genes, and the products are the proteins essential for various functions in our bodies. One of the key findings is that a protein called CPSF6 plays a crucial role in this tailoring process. We found that when CPSF6 isn't working properly, it can lead to a different version of the product - in this case, a protein that might behave differently. These alterations can affect various bodily systems, including our brains, hearts, and skeletal systems. The study shows that understanding how CPSF6 functions could open up new ways to tackle diseases linked to protein malfunction. For example, in certain cancers, the proteins created might be contributing to disease progression. By learning how to control the protein tailoring process, we could potentially intervene and alter the course of such diseases. Overall, our study illuminates a new aspect of how genes and proteins interact, offering another piece to the puzzle of understanding how our bodies work at a fundamental level.

Technical Abstract: Alternative polyadenylation (APA) creates distinct transcripts from the same gene by cleaving the pre-mRNA at poly(A) sites that can lie within the 3' untranslated region (3'UTR), introns, or exons. Most studies focus on APA within the 3'UTR; however, here, we show that CPSF6 insufficiency alters protein levels and causes a developmental syndrome by deregulating APA throughout the transcript. In neonatal humans and zebrafish larvae, CPSF6 insufficiency shifts poly(A) site usage between the 3'UTR and internal sites in a pathway-specific manner. Genes associated with neuronal function undergo mostly intronic APA, reducing their expression, while genes associated with heart and skeletal function mostly undergo 3'UTR APA and are up-regulated. This suggests that, under healthy conditions, cells toggle between internal and 3'UTR APA to modulate protein expression.