Harmful R-loops are prevented via different cell cycle-specific mechanisms.
Marta San Martin-Alonso,María E. Soler-Oliva,María L. García-Rubio,Tatiana García-Muse,Andrés Aguilera +4 more
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TLDR
In this paper, it was shown that R-loops form co-transcriptionally independently of DNA replication and Sen1 is an S-phase-specific R-loop resolvase.Abstract:
Identifying how R-loops are generated is crucial to know how transcription compromises genome integrity. We show by genome-wide analysis of conditional yeast mutants that the THO transcription complex, prevents R-loop formation in G1 and S-phase, whereas the Sen1 DNA-RNA helicase prevents them only in S-phase. Interestingly, damage accumulates asymmetrically downstream of the replication fork in sen1 cells but symmetrically in the hpr1 THO mutant. Our results indicate that: R-loops form co-transcriptionally independently of DNA replication; that THO is a general and cell-cycle independent safeguard against R-loops, and that Sen1, in contrast to previously believed, is an S-phase-specific R-loop resolvase. These conclusions have important implications for the mechanism of R-loop formation and the role of other factors reported to affect on R-loop homeostasis.read more
Citations
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Walking a tightrope: The complex balancing act of R-loops in genome stability.
TL;DR: In this article , the authors discuss the cellular contexts in which R-loops contribute to genomic instability, particularly during DNA replication and double-strand break (DSB) repair.
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The role of chromatin at transcription-replication conflicts as a genome safeguard.
TL;DR: The role of chromatin in TRC occurrence and resolution may help identify the molecular mechanism by which chromatin protects genome integrity, and the causes and physiological relevance of the high mutation rates of Chromatin regulating factors in cancer as discussed by the authors.
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PARP1 associates with R-loops to promote their resolution and genome stability
Natalie Laspata,Parminder Kaur,Sofiane Y Mersaoui,Daniela Muoio,Zhiyan Liu,Maxwell Bannister,Hai Dang Nguyen,Caroline Curry,John M. Pascal,Guy G. Poirier,Hong Wang,Jean-Yves Masson,Elise Fouquerel +12 more
TL;DR: In this paper , the authors demonstrate that PARP1 binds R-loops in vitro and associates with R-loop formation sites in cells which activates its ADP-ribosylation activity.
Journal ArticleDOI
Sen1 is a key regulator of transcription-driven conflicts
TL;DR: The conserved Sen1 helicase not only terminates non-coding transcription but also interacts with the replisome and reportedly resolves genotoxic R-loops as mentioned in this paper .
Journal ArticleDOI
Direct visualization of transcription-replication conflicts reveals post-replicative DNA:RNA hybrids
Henriette Stoy,Katharina Zwicky,Danina Kuster,Kevin S. Lang,Jana Krietsch,Madzia P Crossley,Jonas A. Schmid,Karlene A. Cimprich,Houra Merrikh,Massimo Lopes +9 more
TL;DR: In this paper , the stability of estrogen-induced R-loops on the human genome was visualized directly by electron microscopy (EM) and measured R-loop frequency and size at the single-molecule level.
References
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Journal ArticleDOI
Senataxin: Genome Guardian at the Interface of Transcription and Neurodegeneration
TL;DR: The importance of SETX as a genome guardian in suppressing aberrant R-loop formation is discussed and how SETX mutations can lead to neurodegeneration in AOA2/ALS4 are analysed.
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Histone Mutants Separate R Loop Formation from Genome Instability Induction.
Desiré García-Pichardo,Juan C. Cañas,María L. García-Rubio,Belén Gómez-González,Ana G. Rondón,Andrés Aguilera +5 more
TL;DR: Yeast histone H3 and H4 mutations facilitate R loops but do not cause instability, and a two-step mechanism in which an altered chromatin facilitates R loops and chromatin is modified, including H3S10-P, as a requisite for compromising genome integrity is proposed.
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Human THO-Sin3A interaction reveals new mechanisms to prevent R-loops that cause genome instability
Irene Salas-Armenteros,Carmen Pérez-Calero,Aleix Bayona-Feliu,Emanuela Tumini,Rosa Luna,Andrés Aguilera +5 more
TL;DR: Human THO interacts with the Sin3A histone deacetylase complex to suppress co‐transcriptional R‐loops, DNA damage, and replication impairment, and functional analyses show that histone hypo‐acetylation prevents accumulation of harmful R‐loop formation and RNA‐mediated genomic instability.
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Topoisomerase 1 prevents replication stress at R-loop-enriched transcription termination sites.
Alexy Promonet,Ismael Padioleau,Ismael Padioleau,Yaqun Liu,Lionel A. Sanz,Anna Biernacka,Anne Lyne Schmitz,Magdalena Skrzypczak,Amélie Sarrazin,Clément Mettling,Maga Rowicka,Krzysztof Ginalski,Frédéric Chédin,Chun-Long Chen,Yea-Lih Lin,Philippe Pasero +15 more
TL;DR: These data indicate that fork pausing at the TTS of highly expressed genes containing R-loops prevents head-on conflicts between replication and transcription and maintains genome integrity in a Top1-dependent manner.
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Architecture and nucleic acids recognition mechanism of the THO complex, an mRNP assembly factor
Álvaro Peña,Kamil Gewartowski,Kamil Gewartowski,Seweryn Mroczek,Seweryn Mroczek,Jorge Cuéllar,Aleksandra Szykowska,Aleksandra Szykowska,Andrzej Prokop,Andrzej Prokop,Mariusz Czarnocki-Cieciura,Mariusz Czarnocki-Cieciura,Jan Piwowarski,Cristina Tous,Andrés Aguilera,José L. Carrascosa,José M. Valpuesta,Andrzej Dziembowski,Andrzej Dziembowski +18 more
TL;DR: It is shown that THO directly interacts with nucleic acids through the unfolded C‐terminal region of Tho2, whose removal reduces THO recruitment to active chromatin leading to mRNA biogenesis defects.