R-Loops in Proliferating Cells but Not in the Brain: Implications for AOA2 and Other Autosomal Recessive Ataxias

Yeo, Abrey J.; Bécherel, Olivier J.; Luff, John; Cullen, Jason K.; Wongsurawat, Thidathip; Jenjaroenpoon, Piroon; Kuznetsov, Vladimir A.; McKinnon, Peter J.; Lavin, Martin F.

doi:10.1371/journal.pone.0090219

Cited by 57 publications

(53 citation statements)

References 56 publications

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“…Using this system, we observed that nuclear foci of this mutant and not wild‐type RNase H significantly accumulated in cells depleted of Ddx19 compared to control cells (Fig EV4D). R‐loops were observed throughout the nucleus, highly enriched in the nucleolar compartment, similar to the pattern previously observed in cells depleted of senataxin (Yeo et al , ), and consistent with the pattern of γH2AX staining and 53BP1 foci (Fig C). Of note, in cells depleted of Nxf1, R‐loops accumulated mainly close to the nuclear periphery (Fig A, upper panel), again consistent with the observed pattern of 53BP1 foci upon Nxf1 downregulation (Fig B and C), and in line with a function of Nxf1 at the nuclear face of the nuclear pore.…”

Section: Resultssupporting

confidence: 89%

An ATR‐dependent function for the Ddx19 RNA helicase in nuclear R‐loop metabolism

et al. 2017

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Coordination between transcription and replication is crucial in the maintenance of genome integrity. Disturbance of these processes leads to accumulation of aberrant DNA:RNA hybrids (R-loops) that, if unresolved, generate DNA damage and genomic instability. Here we report a novel, unexpected role for the nucleopore-associated mRNA export factor Ddx19 in removing nuclear R-loops formed upon replication stress or DNA damage. We show, in live cells, that Ddx19 transiently relocalizes from the nucleopore to the nucleus upon DNA damage, in an ATR/Chk1-dependent manner, and that Ddx19 nuclear relocalization is required to clear R-loops. Ddx19 depletion induces R-loop accumulation, proliferation-dependent DNA damage and defects in replication fork progression. Further, we show that Ddx19 resolves R-loops via its helicase activity. Furthermore, mutation of a residue phosphorylated by Chk1 in Ddx19 disrupts its interaction with Nup214 and allows its nuclear relocalization. Finally, we show that Ddx19operates in resolving R-loops independently of the RNA helicase senataxin. Altogether these observations put forward a novel, ATR-dependent function for Ddx19 in R-loop metabolism to preserve genome integrity in mammalian cells.

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Section: Resultssupporting

confidence: 89%

An ATR‐dependent function for the Ddx19 RNA helicase in nuclear R‐loop metabolism

et al. 2017

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“…In silico analysis of the human genome identified a high number of RLFS (245 181) in 59% well-annotated genes (18). Consistent with these predictions, several recent genome-wide experimental studies mapped thousands of RNA:DNA hybridization signals distributed along human and mouse genomes and demonstrated that R-loops can be formed not only in the gene body but also in the upstream promoter regions (9–11) and transcription pause sites located downstream of the poly(A) signal (9,10,12,13,19). Formation of these R-loops in proximal promoter regions was shown to be involved in transcription initiation or elongation (9) and the recruitment of key pluripotency regulators (11).…”

Section: Introductionmentioning

confidence: 63%

R-loopDB: a database for R-loop forming sequences (RLFS) and R-loops

et al. 2016

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R-loopDB (http://rloop.bii.a-star.edu.sg) was originally constructed as a collection of computationally predicted R-loop forming sequences (RLFSs) in the human genic regions. The renewed R-loopDB provides updates, improvements and new options, including access to recent experimental data. It includes genome-scale prediction of RLFSs for humans, six other animals and yeast. Using the extended quantitative model of RLFSs (QmRLFS), we significantly increased the number of RLFSs predicted in the human genes and identified RLFSs in other organism genomes. R-loopDB allows searching of RLFSs in the genes and in the 2 kb upstream and downstream flanking sequences of any gene. R-loopDB exploits the Ensembl gene annotation system, providing users with chromosome coordinates, sequences, gene and genomic data of the 1 565 795 RLFSs distributed in 121 056 genic or proximal gene regions of the covered organisms. It provides a comprehensive annotation of Ensembl RLFS-positive genes including 93 454 protein coding genes, 12 480 long non-coding RNA and 7 568 small non-coding RNA genes and 7 554 pseudogenes. Using new interface and genome viewers of R-loopDB, users can search the gene(s) in multiple species with keywords in a single query. R-loopDB provides tools to carry out comparative evolution and genome-scale analyses in R-loop biology.

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“…However, a direct link between the regulation of R-loops and disease etiology is still missing. In fact mouse models that try to recapitulate the human disease show elevated R-loop formation, DNA damage and apoptosis in proliferating cells, but not in post-mitotic cells, like the brain neurons [43]. It is still possible that neurons are particularly sensitive to low levels of R-loop, or R-loop formation in other tissues indirectly impacts neuron function.…”

Section: R-loops In Human Diseasesmentioning

confidence: 99%

The Yin and Yang of R-loop biology

Costantino¹,

Koshland²

2015

Current Opinion in Cell Biology

119

111

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RNA performs diverse functions in cells, directing translation, modulating transcription and catalyzing enzymatic reactions. Remarkably RNA can also anneal to its genomic template co- or post-transcriptionally to generate an RNA-DNA hybrid and a displaced single-stranded DNA. These unusual nucleic acid structures are called R-loops. Studies in the last decades concentrated on the detrimental effects of R-loop formation, particularly on genome stability. In fact, R-loops are thought to play a role in several human diseases like cancer and neurodegenerative syndromes. But recent data has revealed that R-loops can also have a positive impact on cell processes, like regulating gene expression, chromosome structure and DNA repair. Here we summarize our current understanding of the formation and dissolution of R-loops, and discuss their negative and positive impact on genome structure and function.

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R-Loops in Proliferating Cells but Not in the Brain: Implications for AOA2 and Other Autosomal Recessive Ataxias

Cited by 57 publications

References 56 publications

An ATR‐dependent function for the Ddx19 RNA helicase in nuclear R‐loop metabolism

An ATR‐dependent function for the Ddx19 RNA helicase in nuclear R‐loop metabolism

R-loopDB: a database for R-loop forming sequences (RLFS) and R-loops

The Yin and Yang of R-loop biology

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