# Integrative analysis of RNA binding proteins identifies DDX55 as a novel regulator of 3’UTR isoform diversity

## TL;DR

This study identifies DDX55 as a new regulator of 3’UTR isoform diversity, which affects gene expression through alternative polyadenylation.

## Contribution

The study introduces DDX55 as a novel RNA binding protein involved in regulating 3’UTR isoform diversity.

## Key findings

- DDX55 regulates 3’UTR isoform diversity, particularly at polyadenylation sites with RNA secondary structure features.
- Depletion of RNA binding proteins leads to widespread changes in 3’UTR patterns.
- The study uncovers potential new regulators of 3’UTR processing and stability.

## Abstract

The 3’ untranslated regions (3’UTRs) of mRNAs play a critical role in controlling gene expression and function because they contain binding sites for microRNAs and RNA binding proteins (RBPs) that alter mRNA stability, localization, and translation. Most mRNA 3’ ends contain multiple polyadenylation sites (PAS) that can be utilized in condition-specific manners, a process known as alternative polyadenylation (APA). However, the mechanisms driving the regulation of APA remain poorly characterized.

By integrating a large set of over 500 RNA binding protein (RBP) depletion and binding experiments across two cell lines generated by the ENCODE consortium, we uncovered many RBPs in each cell type whose depletion leads to widespread alteration of 3’UTR patterns. These include not only known regulators of APA, but also many putative novel regulators of 3’UTR isoform expression. We focused our analysis on the largely unstudied DEAD box RNA helicase DDX55, and validated its novel role in 3’UTR isoform regulation using molecular assays and targeted 3’ end sequencing experiments.

Our findings identify DDX55 as a new regulator of APA, particularly at PAS that contain features of RNA secondary structure. Our data also suggest additional previously unrecognized regulators of 3’UTR processing and differential stability.

The online version contains supplementary material available at 10.1186/s13059-025-03852-8.