Elongation Factor TFIIS Prevents Transcription Stress and R-Loop Accumulation to Maintain Genome Stability

Zatreanu, Diana; Han, Zhong Chao; Mitter, Richard; Tumini, Emanuela; Williams, Hannah; Gregersen, Lea H.; Dirac-Svejstrup, A. Barbara; Roma, Stefania; Stewart, Aengus; Aguilera, Andrés; Svejstrup, Jesper Q.

doi:10.1016/j.molcel.2019.07.037

Cited by 97 publications

(88 citation statements)

References 64 publications

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“…If these roadblocks are not resolved, collisions with the replication machinery will lead to replication fork breakdown and DNA strand breaks. Important factors have been identified that prevent and resolve R-loops, including the RNAPII activator CDK9 and the RNA:DNA hybrid endonuclease RNase H1 [27][28][29][30][31][32][33][34][35][36][37] .…”

Section: Introductionmentioning

confidence: 99%

BRD4 Prevents R-Loop Formation and Transcription-Replication Conflicts by Ensuring Efficient Transcription Elongation

Edwards

Maganti

Tanksley

et al. 2019

Preprint

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Effective spatio-temporal control of transcription and replication during S-phase is paramount to maintain genomic integrity and cell survival. Deregulation of these systems can lead to conflicts between the transcription and replication machinery leading to DNA damage. BRD4, a BET bromodomain protein and known transcriptional regulator, interacts with P-TEFb to ensure efficient transcriptional elongation by stimulating phosphorylation of RNA Polymerase II (RNAPII). Here we report that disruption of BET bromodomain protein function causes DNA damage that correlates with RNAPII-dependent transcript elongation and occurs preferentially in S-phase cells.BET bromodomain inhibition also causes accumulation of RNA:DNA hybrids (R-loops), which are known to lead to transcription-replication conflicts, DNA damage, and cell death. Furthermore, we show that resolution of R-loops abrogates BET-bromodomain inhibitor-induced DNA damage, and that BET-bromodomain inhibition induces both Rloops and DNA damage at sites of BRD4 occupancy. Finally, we see that the BRD4 Cterminal domain, which interacts with P-TEFb, is required to prevent R-loop formation and DNA damage caused by BET bromodomain inhibition. Together, these findings demonstrate that BET bromodomain inhibitors can damage DNA via induction of Rloops in highly replicative cells.

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Section: Introductionmentioning

confidence: 99%

BRD4 Prevents R-Loop Formation and Transcription-Replication Conflicts by Ensuring Efficient Transcription Elongation

Edwards

Maganti

Tanksley

et al. 2019

Preprint

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“…We found additional proteins described to bind to R-loops (99) and prevent their formation (100) in the BioID dataset. These include members of the spliceosome (101,102), the exosome (103), topoisomerase 1 (104) and an associated bromodomain-containing protein BRD2 (105), transcription elongation factor TFIIS (106) or FACT (107). These proteins are involved in the resolution of genome maintenance conflicts caused by R-loop formation in mammals.…”

Section: Discussionmentioning

confidence: 99%

A DOT1B/Ribonuclease H2 protein complex is involved in R-loop processing, genomic integrity and antigenic variation inTrypanosoma brucei

Eisenhuth

Vellmer

Butter

et al. 2020

Preprint

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The parasite Trypanosoma brucei periodically changes the expression of protective variant surface glycoproteins (VSGs) to evade its host's immune system in a process known as antigenic variation.One route to change VSG expression is the transcriptional activation of a previously silent VSG expression site (ES), a subtelomeric region containing the VSG genes. Homologous recombination of a different VSG from a large reservoir into the active ES represents another route. The conserved histone methyltransferase DOT1B is involved in transcriptional silencing of inactive ES and influences ES switching kinetics. The molecular machinery that enables DOT1B to execute these regulatory functions remains elusive, however. To better understand DOT1B-mediated regulatory processes, we purified DOT1B-associated proteins using complementary biochemical approaches. We identified several novel DOT1B-interactors. One of these was the Ribonuclease H2 complex, previously shown to resolve RNA-DNA hybrids, maintain genome integrity, and play a role in antigenic variation. Our study revealed that DOT1B depletion results in an increase in RNA-DNA hybrids, accumulation of DNA damage and recombination-based ES switching events. Surprisingly, a similar pattern of VSG deregulation was observed in Ribonuclease H2 mutants. We propose that both proteins act together in resolving R-loops to ensure genome integrity and contribute to the tightly-regulated process of antigenic variation.

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“…Depletion of either RNase H, SETX or EXOSC10 results in increased levels of DNA:RNA hybrids and genomic instability, as described above, [ 29,49,54,63,64 ] which suggests that both RNase H and the SETX‐exosome system are required to prevent the accumulation of DNA:RNA hybrids in the DNA. However, the reason why both nucleolytic systems are needed is not understood yet.…”

Section: Resolution Of Dna:rna Hybrids At Dsbsmentioning

confidence: 94%

“…[ 51 ] However, R‐loops can cause genome instability and, during transcription, RNA binding proteins and processing factors assemble with the nascent RNA and prevent R‐loop formation. [ 44,52–55 ]…”

Section: Dilncrnas Produced At Dsbs Engage In Dna:rna Hybrid Formationmentioning

confidence: 99%

RNA at DNA Double‐Strand Breaks: The Challenge of Dealing with DNA:RNA Hybrids

2020

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RNA polymerase II is recruited to DNA double-strand breaks (DSBs), transcribes the sequences that flank the break and produces a novel RNA type that has been termed damage-induced long non-coding RNA (dilncRNA). DilncRNAs can be processed into short, miRNA-like molecules or degraded by different ribonucleases. They can also form double-stranded RNAs or DNA:RNA hybrids. The DNA:RNA hybrids formed at DSBs contribute to the recruitment of repair factors during the early steps of homologous recombination (HR) and, in this way, contribute to the accuracy of the DNA repair. However, if not resolved, the DNA:RNA hybrids are highly mutagenic and prevent the recruitment of later HR factors. Here recent discoveries about the synthesis, processing, and degradation of dilncRNAs are revised. The focus is on RNA clearance, a necessary step for the successful repair of DSBs and the aim is to reconcile contradictory findings on the effects of dilncRNAs and DNA:RNA hybrids in HR.

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Elongation Factor TFIIS Prevents Transcription Stress and R-Loop Accumulation to Maintain Genome Stability

Cited by 97 publications

References 64 publications

BRD4 Prevents R-Loop Formation and Transcription-Replication Conflicts by Ensuring Efficient Transcription Elongation

BRD4 Prevents R-Loop Formation and Transcription-Replication Conflicts by Ensuring Efficient Transcription Elongation

A DOT1B/Ribonuclease H2 protein complex is involved in R-loop processing, genomic integrity and antigenic variation inTrypanosoma brucei

RNA at DNA Double‐Strand Breaks: The Challenge of Dealing with DNA:RNA Hybrids

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