UAP56/DDX39B is a major cotranscriptional RNA–DNA helicase that unwinds harmful R loops genome-wide
- Carmen Pérez-Calero1,
- Aleix Bayona-Feliu1,
- Xiaoyu Xue2,3,
- Sonia I. Barroso1,
- Sergio Muñoz1,
- Víctor M. González-Basallote1,
- Patrick Sung2,4 and
- Andrés Aguilera1
- 1Centro Andaluz de Biología Molecular y Medicina Regenerativa (CABIMER) Universidad de Sevilla-CSIC-Universidad Pablo de Olavide, Sevilla 41092, Spain;
- 2Molecular Biophysics and Biochemistry, School of Medicine, University of Yale, New Haven, Connecticut 06510, USA;
- 3Department of Chemistry and Biochemistry, Texas State University, San Marcos, Texas 78666, USA;
- 4Department of Biochemistry and Structural Biology, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229, USA
- Corresponding author: aguilo{at}us.es
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
- double-strand breaks
- genome instability
- R loops
- RNA–DNA helicase
- RNA–DNA hybrids
- replication fork stalling
- UAP56/DDX39B
Footnotes
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Supplemental material is available for this article.
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Article published online ahead of print. Article and publication date are online at http://www.genesdev.org/cgi/doi/10.1101/gad.336024.119.
- Received December 13, 2019.
- Accepted April 20, 2020.
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