A double-edged sword: R loops as threats to genome integrity and powerful regulators of gene expression

Skourti-Stathaki, Konstantina; Proudfoot, Nick J.

doi:10.1101/gad.242990.114

Cited by 458 publications

(450 citation statements)

References 127 publications

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“…More specifically, FUS participates in both homologous recombination (HR) and nonhomologous end joining (NHEJ)-directed DSB repair (6,7). The evidence suggesting a role for FUS in DNA repair is particularly intriguing for ALS pathogenesis, given growing evidence that RNA binding proteins are active in the prevention and repair of transcription-associated DNA damage (8)(9)(10)(11)(12). Other ALS-related RNAbinding proteins like SETX, EWSR1, and TAF15 have also been linked to DNA damage and repair, further suggesting the importance of a breakdown in this process in ALS pathogenesis (11,(13)(14)(15)(16).…”

Section: Dna Damage Response | Als | Transcription | R Loopmentioning

confidence: 99%

Two familial ALS proteins function in prevention/repair of transcription-associated DNA damage

Hill

Mordes

Cameron

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

107

119

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Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron dysfunction disease that leads to paralysis and death. There is currently no established molecular pathogenesis pathway. Multiple proteins involved in RNA processing are linked to ALS, including FUS and TDP43, and we propose a disease mechanism in which loss of function of at least one of these proteins leads to an accumulation of transcription-associated DNA damage contributing to motor neuron cell death and progressive neurological symptoms. In support of this hypothesis, we find that FUS or TDP43 depletion leads to increased sensitivity to a transcription-arresting agent due to increased DNA damage. Thus, these proteins normally contribute to the prevention or repair of transcription-associated DNA damage. In addition, both FUS and TDP43 colocalize with active RNA polymerase II at sites of DNA damage along with the DNA damage repair protein, BRCA1, and FUS and TDP43 participate in the prevention or repair of R loopassociated DNA damage, a manifestation of aberrant transcription and/or RNA processing. Gaining a better understanding of the role(s) that FUS and TDP43 play in transcription-associated DNA damage could shed light on the mechanisms underlying ALS pathogenesis.A myotrophic lateral sclerosis (ALS) is a disease of both upper and lower motor neuron dysfunction that leads to progressive paralysis and eventually death due to respiratory failure. No single model of ALS disease pathogenesis has been revealed; however, multiple disease-associated genes are known (1). The variation in function of these genes suggests that there may be multiple ALS molecular subtypes. That said, the familial ALS gene product list is also enriched in protein groups with related functions.Mutations in multiple RNA processing genes, including FUS (FUS RNA-binding protein), TDP43 (TAR DNA-binding protein), SETX (senataxin), TAF15 (TATA box-binding protein-associated factor 15), EWSR1 (EWS RNA-binding protein 1), HNRNPA1 (heterogeneous nuclear ribonucleoprotein A1), and HNRNPA2B1 (heterogeneous nuclear ribonucleoprotein A2/B1), among others, give rise to familial ALS (fALS) (1). FUS and TDP43 are currently the best studied, given that mutations in these genes lead to classic histologic findings in ALS neural tissue and that similar histologic findings can be found in neural tissue of sporadic ALS cases (2). At autopsy, cytoplasmic TDP43 inclusions are found in ALS motor neurons from patients with (i) TDP43 mutations and (ii) sporadic ALS (i.e., patients with no FUS, TDP43, or other known pathogenic mutation) (2). They are also present in neurons in various parts of the brains of patients with either sporadic or familial versions of the ALS-related disorder, fronto-temporal lobar dementia (FTLD) (2). At autopsy, FUS inclusions were detected in the cytoplasm of motor neurons of FUS mutation-bearing fALS patients and in the cytoplasm of neurons in various regions of the brain in some FTLD patients (2).FUS and TDP43 exhibit a wide range of functions, most of which involv...

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Section: Dna Damage Response | Als | Transcription | R Loopmentioning

confidence: 99%

Two familial ALS proteins function in prevention/repair of transcription-associated DNA damage

Hill

Mordes

Cameron

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

107

119

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“…R-loops have been shown to both stabilize and destabilize the genome depending on the context. 133,134 The characteristics and mechanisms that determine whether an R-loop is beneficial or detrimental to the genome are unknown. SMN may contribute to this determination through its interaction with SETX.…”

Section: Smn and Transcriptional Regulationmentioning

confidence: 99%

SMN - A chaperone for nuclear RNP social occasions?

2016

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Survival Motor Neuron (SMN) protein localizes to both the nucleus and the cytoplasm. Cytoplasmic SMN is diffusely localized in large oligomeric complexes with core member proteins, called Gemins. Biochemical and cell biological studies have demonstrated that the SMN complex is required for the cytoplasmic assembly and nuclear transport of Sm-class ribonucleoproteins (RNPs). Nuclear SMN accumulates with spliceosomal small nuclear (sn)RNPs in Cajal bodies, sub-domains involved in multiple facets of snRNP maturation. Thus, the SMN complex forms stable associations with both nuclear and cytoplasmic snRNPs, and plays a critical role in their biogenesis. In this review, we focus on potential functions of the nuclear SMN complex, with particular emphasis on its role within the Cajal body.

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“…Resolution of R-loops in vivo would be accomplished by the activity of endogenous RNase H enzymes as well as RNA-DNA helicases such as Sen1/Senataxin. 70,76,77 It is also likely that these R-loops are cleared by transcription of another lncRNA molecule. The latter is supported by the fact that high levels of transcription correlate with the presence of R-loops in wild type cells, 78 which would be predicted to interfere with transcription if these structures were static.…”

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confidence: 99%

“…67,68 These structures can form in cis 60 or trans 69 in vivo, either by "threading back" of nascent RNAs during transcription by RNA Pol II, through the action of the homologous recombination machinery, or associated RNA-binding proteins as in the case of CRISPR. 60,70,71 Given that RNP assembly defects cause R-loops, 60,70 we speculated that loss of DBP2 might promote formation of these structures between the GAL lncRNAs and GAL gene promoters. To test this, we asked if ectopic expression of human RNAse H1 in dbp2D cells would prevent rapid induction of the GAL genes by the GAL lncRNAs.…”

mentioning

confidence: 99%

LncRNAs: Bridging environmental sensing and gene expression

2016

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The survival of all organisms is dependent on complex, coordinated responses to environmental cues. Non-coding RNAs have been identified as major players in regulation of gene expression, with recent evidence supporting roles for long non-coding (lnc)RNAs in both transcriptional and post-transcriptional control. Evidence from our laboratory shows that lncRNAs have the ability to form hybridized structures called R-loops with specific DNA target sequences in S. cerevisiae, thereby modulating gene expression. In this Point of View, we provide an overview of the nature of lncRNA-mediated control of gene expression in the context of our studies using the GAL gene cluster as a model for controlling the timing of transcription.

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A double-edged sword: R loops as threats to genome integrity and powerful regulators of gene expression

Cited by 458 publications

References 127 publications

Two familial ALS proteins function in prevention/repair of transcription-associated DNA damage

Two familial ALS proteins function in prevention/repair of transcription-associated DNA damage

SMN - A chaperone for nuclear RNP social occasions?

LncRNAs: Bridging environmental sensing and gene expression

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