DHX9 helicase promotes R-loop formation in cells with impaired RNA splicing

Nat Commun. 2018 Oct 19;9(1):4346. doi: 10.1038/s41467-018-06677-1.

Abstract

R-loops are stable nucleic acid structures that have important physiological functions, but which also pose a significant threat to genomic stability. Increased R-loops cause replication stress and chromosome fragility and have been associated with diseases such as neurodegeneration and cancer. Although excessive R-loops are a feature of cells that are defective in RNA processing, what causes them to form is unclear. Here, we demonstrate that DHX9 (RNA helicase A) promotes the formation of pathological and non-pathological R-loops. In the absence of splicing factors, formation of R-loops correlates with the prolonged association of DHX9 with RNA Polymerase II (RNA Pol II). This leads to the production of DNA-RNA hybrid, which traps RNA Pol II on chromatin with the potential to block DNA replication. Our data provide a molecular mechanism for the formation of R-loops that is relevant to neurodegenerative diseases and cancers in which deregulated RNA processing is a feature.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • DEAD-box RNA Helicases / chemistry
  • DEAD-box RNA Helicases / physiology*
  • DNA Replication / physiology
  • Genomic Instability
  • HeLa Cells
  • Humans
  • Models, Molecular*
  • Neoplasm Proteins / chemistry
  • Neoplasm Proteins / physiology*
  • Nucleic Acid Conformation
  • RNA Polymerase II / chemistry
  • RNA Polymerase II / metabolism
  • RNA Polymerase II / physiology
  • RNA Splicing / physiology*
  • RNA Splicing Factors / chemistry
  • RNA Splicing Factors / metabolism

Substances

  • Neoplasm Proteins
  • RNA Splicing Factors
  • RNA Polymerase II
  • DHX9 protein, human
  • DEAD-box RNA Helicases