Splicing quality control mediated by DHX15 and its G-patch activator, SUGP1

ABSTRACT Pre-mRNA splicing is surveilled at different stages by quality control (QC) mechanisms. The leukemia-associated DExH-box family helicase h DHX15/ sc Prp43, is known to disassemble spliceosomes after splicing. Here, using rapid protein depletion and analysis of nascent and mature RNA to enrich for direct effects, we identified a widespread splicing QC function for DHX15 in human cells, consistent with recent in vitro studies. We found that suboptimal introns with weak splice sites, multiple branch points, and cryptic introns are repressed by DHX15, suggesting a general role in promoting splicing fidelity. We identified SUGP1 as a G-patch factor that activates DHX15’s splicing QC function. This interaction is dependent on both DHX15’s ATPase activity and on SUGP1’s ULM domain. Together, our results support a model in which DHX15 plays a major role in splicing QC when recruited and activated by SUGP1.