UAP56/DDX39B Is a Major Cotranscriptional RNA-DNA Helicase That Unwinds Harmful R Loops Genome-Wide

Genes Dev. 2020 Jul 1;34(13-14):898-912. doi: 10.1101/gad.336024.119. Epub 2020 May 21.

Abstract

Nonscheduled R loops represent a major source of DNA damage and replication stress. Cells have different ways to prevent R-loop accumulation. One mechanism relies on the conserved THO complex in association with cotranscriptional RNA processing factors including the RNA-dependent ATPase UAP56/DDX39B and histone modifiers such as the SIN3 deacetylase in humans. We investigated the function of UAP56/DDX39B in R-loop removal. We show that UAP56 depletion causes R-loop accumulation, R-loop-mediated genome instability, and replication fork stalling. We demonstrate an RNA-DNA helicase activity in UAP56 and show that its overexpression suppresses R loops and genome instability induced by depleting five different unrelated factors. UAP56/DDX39B localizes to active chromatin and prevents the accumulation of RNA-DNA hybrids over the entire genome. We propose that, in addition to its RNA processing role, UAP56/DDX39B is a key helicase required to eliminate harmful cotranscriptional RNA structures that otherwise would block transcription and replication.

Keywords: R loops; RNA–DNA helicase; RNA–DNA hybrids; UAP56/DDX39B; double-strand breaks; genome instability; replication fork stalling.