Sen1 is a key regulator of transcription-driven conflicts

Aiello, Umberto; Challal, Drice; Wentzinger, Griselda; Lengronne, Armelle; Appanah, Rowin; Pasero, Philippe; Palancade, Benoı̂t; Libri, Domenico

doi:10.1016/j.molcel.2022.06.021

Cited by 23 publications

(21 citation statements)

References 50 publications

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“…Our result that RNAPII stalling is suppressed upon RNase H1 overexpression suggests that digestion of the RNA of a co-transcriptional RNA:DNA hybrid could release stalled RNAPII, leading to the observed suppression of TRCs and breaks. Consistent with our results, a recent study observed increased RNAPII stalling in a Senataxin mutant ( sen1-3 ) at the rDNA replication fork barrier (rRFB) [ 73 ]. Stalling at the rRFB in sen1-3 was suppressed upon overexpression of human RNase H1 [ 73 ].…”

Section: Discussionsupporting

confidence: 92%

“…Consistent with our results, a recent study observed increased RNAPII stalling in a Senataxin mutant ( sen1-3 ) at the rDNA replication fork barrier (rRFB) [ 73 ]. Stalling at the rRFB in sen1-3 was suppressed upon overexpression of human RNase H1 [ 73 ]. Also similar to our model, another recent study proposed that in sen1 mutants, the main replication barrier is a RNAPII complex trapped on the DNA template due to stable R-loop formation [ 74 ].…”

Section: Discussionsupporting

confidence: 92%

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The RNA export and RNA decay complexes THO and TRAMP prevent transcription-replication conflicts, DNA breaks, and CAG repeat contractions

Brown

Fair

et al. 2022

PLoS Biol

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Expansion of structure-forming CAG/CTG repetitive sequences is the cause of several neurodegenerative disorders and deletion of repeats is a potential therapeutic strategy. Transcription-associated mechanisms are known to cause CAG repeat instability. In this study, we discovered that Thp2, an RNA export factor and member of the THO (suppressors of transcriptional defects of hpr1Δ by overexpression) complex, and Trf4, a key component of the TRAMP (Trf4/5-Air1/2-Mtr4 polyadenylation) complex involved in nuclear RNA polyadenylation and degradation, are necessary to prevent CAG fragility and repeat contractions in a Saccharomyces cerevisiae model system. Depletion of both Thp2 and Trf4 proteins causes a highly synergistic increase in CAG repeat fragility, indicating a complementary role of the THO and TRAMP complexes in preventing genome instability. Loss of either Thp2 or Trf4 causes an increase in RNA polymerase stalling at the CAG repeats and other genomic loci, as well as genome-wide transcription-replication conflicts (TRCs), implicating TRCs as a cause of CAG fragility and instability in their absence. Analysis of the effect of RNase H1 overexpression on CAG fragility, RNAPII stalling, and TRCs suggests that RNAPII stalling with associated R-loops are the main cause of CAG fragility in the thp2Δ mutants. In contrast, CAG fragility and TRCs in the trf4Δ mutant can be compensated for by RPA overexpression, suggesting that excess unprocessed RNA in TRAMP4 mutants leads to reduced RPA availability and high levels of TRCs. Our results show the importance of RNA surveillance pathways in preventing RNAPII stalling, TRCs, and DNA breaks, and show that RNA export and RNA decay factors work collaboratively to maintain genome stability.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionsupporting

confidence: 92%

The RNA export and RNA decay complexes THO and TRAMP prevent transcription-replication conflicts, DNA breaks, and CAG repeat contractions

Brown

Fair

et al. 2022

PLoS Biol

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“…Importantly, we have demonstrated that, akin to its yeast homologue Sen1, SETX is a genuine transcription termination factor, which directly induces the release of paused RNAPIIs and associated transcripts from the DNA (Figures 5 and 7). We therefore propose that SETX uses its ability to dislodge RNAPII from the DNA to regulate gene expression and possibly to remove RNAPIIs from TRC sites, as recently showed for its yeast counterpart (56). Interestingly, we have observed that SETX displays a clear transcription termination activity on bovine RNAPII, which is 99.9 % identical to human RNAPII (78) but not on the more divergent budding yeast RNAPII (Figure 5).…”

Section: Discussionsupporting

confidence: 71%

Section: Discussionmentioning

confidence: 73%

“…When Sen1 translocates on the nascent RNA and encounters the transcribing RNAPII, it induces the dissociation of the elongation complex, thereby releasing the RNAPII and the transcript from the DNA (48,51). During S-phase, Sen1 associates with the replication fork (52,53) and uses its transcription termination activity to remove RNAPIIs and associated R-loops from TRC sites to aid fork progression (54)(55)(56).…”

Section: Introductionmentioning

confidence: 99%

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Human senataxin is a bona fide R-loop resolving enzyme and transcription termination factor

Hašanová

Klapstova

Porrúa

et al. 2022

Preprint

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Prolonged pausing of the transcription machinery may lead to the formation of three-stranded nucleic acid structures, called R-loops, typically resulting from the annealing of the nascent RNA with the template DNA. Unscheduled persistence of R-loops and RNA polymerases may interfere with transcription itself and other essential processes such as DNA replication and repair. Senataxin (SETX) is a putative helicase, mutated in two neurodegenerative disorders, which has been implicated in the control of R-loop accumulation and in transcription termination. However, understanding the precise role of SETX in these processes has been precluded by the absence of a direct characterisation of SETX biochemical activities. Here, we purify and characterise the helicase domain of SETX in parallel with its yeast orthologue, Sen1. Importantly, we show that SETX is a bona fide helicase with the ability to resolve R-loops. Furthermore, SETX has retained the transcription termination activity of Sen1 but functions in a species-specific manner. Finally, subsequent characterisation of two SETX variants harbouring disease-associated mutations shed light into the effect of such mutations on SETX folding and biochemical properties. Altogether, these results broaden our understanding of SETX function in gene expression and the maintenance of genome integrity and provide clues to elucidate the molecular basis of SETX-associated neurodegenerative diseases.

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Looping forward: exploring R‐loop processing and therapeutic potential

Stratigi,

Siametis,

Garinis

2024

FEBS Letters

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Recently, there has been increasing interest in the complex relationship between transcription and genome stability, with specific attention directed toward the physiological significance of molecular structures known as R‐loops. These structures arise when an RNA strand invades into the DNA duplex, and their formation is involved in a wide range of regulatory functions affecting gene expression, DNA repair processes or cell homeostasis. The persistent presence of R‐loops, if not effectively removed, contributes to genome instability, underscoring the significance of the factors responsible for their resolution and modification. In this review, we provide a comprehensive overview of how R‐loop processing can drive either a beneficial or a harmful outcome. Additionally, we explore the potential for manipulating such structures to devise rationalized therapeutic strategies targeting the aberrant accumulation of R‐loops.

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Sen1 is a key regulator of transcription-driven conflicts

Cited by 23 publications

References 50 publications

The RNA export and RNA decay complexes THO and TRAMP prevent transcription-replication conflicts, DNA breaks, and CAG repeat contractions

The RNA export and RNA decay complexes THO and TRAMP prevent transcription-replication conflicts, DNA breaks, and CAG repeat contractions

Human senataxin is a bona fide R-loop resolving enzyme and transcription termination factor

Looping forward: exploring R‐loop processing and therapeutic potential

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