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

Prasun Chakraborty, Jeffrey Huang, Kevin Hiom (Lead / Corresponding author)

Research output: Contribution to journalArticle

5 Citations (Scopus)
82 Downloads (Pure)

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 PolII 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.
Original languageEnglish
Article number4346
Pages (from-to)1-14
Number of pages14
JournalNature Communications
Volume9
Issue number9
DOIs
Publication statusPublished - 19 Oct 2018

Fingerprint

RNA Splicing
splicing
RNA
cells
Chromosome Fragility
Neurodegenerative diseases
RNA Helicases
RNA Polymerase II
Genomic Instability
DNA
Chromosomes
deoxyribonucleic acid
Processing
cancer
DNA Replication
Neurodegenerative Diseases
Nucleic Acids
Chromatin
Neoplasms
chromatin

Cite this

@article{e8fccec88d7747ca9a48e72209d9caaa,
title = "DHX9 Helicase promotes R-loop formation in cells with impaired RNA splicing",
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 PolII 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.",
author = "Prasun Chakraborty and Jeffrey Huang and Kevin Hiom",
note = "We acknowledge funding for this work from BBSRC grant BB/P021387/1 and Cancer Research UK grant A12769.",
year = "2018",
month = "10",
day = "19",
doi = "10.1038/s41467-018-06677-1",
language = "English",
volume = "9",
pages = "1--14",
journal = "Nature Communications",
issn = "2041-1723",
publisher = "Nature Publishing Group",
number = "9",

}

TY - JOUR

T1 - DHX9 Helicase promotes R-loop formation in cells with impaired RNA splicing

AU - Chakraborty, Prasun

AU - Huang, Jeffrey

AU - Hiom, Kevin

N1 - We acknowledge funding for this work from BBSRC grant BB/P021387/1 and Cancer Research UK grant A12769.

PY - 2018/10/19

Y1 - 2018/10/19

N2 - 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 PolII 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.

AB - 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 PolII 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.

U2 - 10.1038/s41467-018-06677-1

DO - 10.1038/s41467-018-06677-1

M3 - Article

VL - 9

SP - 1

EP - 14

JO - Nature Communications

JF - Nature Communications

SN - 2041-1723

IS - 9

M1 - 4346

ER -