Harmful R loops are prevented via different cell cycle specific mechanisms
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA670705 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR12879671_1.fastq.gz | Fastqsanger.gz | |||
| SRR12879671_2.fastq.gz | Fastqsanger.gz | |||
| SRR12879672_1.fastq.gz | Fastqsanger.gz | |||
| SRR12879672_2.fastq.gz | Fastqsanger.gz | |||
| SRR12879673_1.fastq.gz | Fastqsanger.gz |
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Project description:R loops induce transcription-replication (T-R) conflicts, but recent reports have suggested that R-loops are caused by T-R conflicts. Identifying how R loops are generated is crucial to know how transcription compromise genome integrity. Genome-wide analyses of conditional yeast mutants reveal that transcription factors, such as the THO 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 RF in sen1 cells but symmetrically in the hpr1 THO mutant. Our results unambiguously indicate that: R loops forms co-transcriptionally independently of DNA replication; THO is a general and cell-cycle independent safeguard against R loops, and 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 impact on R loop homeostasis
2021-07-22 | GSE159870 | GEO
Project description: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.
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Project description:Understanding how the assembly of nascent mRNA into a ribonucleoprotein (mRNP) influences R-loop homeostasis is crucial for gaining insights into the cellular mechanisms that prevent genome instability. Here, we identify three RNA-binding proteins, Rie1, Rim4 and She2, whose stoichiometry is important for limiting R-loop accumulation and, consequently, preventing DNA damage. Notably, Rim4 and She2 are overrepresented in mRNPs assembled in the absence of THO. Additionally, we found that an excess of Dis3 impairs exosome function, promoting R-loops, particularly from non-coding RNAs, that causes genomic instability. Our results indicate that mRNP assembly is a precise process that when perturbed by changes in the availability of different RBPs or RNAs, causes R-loop-mediated DNA damage in the cell. These results may have important implications for understanding the mechanism that promotes cancer, as several RBPs are overexpressed in different types of tumors.
2025-06-13 | PXD057248 | Pride
Project description:Non-scheduled R loops represent a major source of DNA damage and replication stress. Cells have different ways to prevent R loop accumulation. One mechanism relies on the conserved THO complex in association with co-transcriptional RNA processing factors including the RNA-dependent ATPase UAP56/DDX39B and histone modifiers such as the SIN3 deacetylase in humans. We investigated the function of UAP56/DDX39B in R loop removal. We show that UAP56 depletion causes R loop accumulation, R loop-mediated genome instability and replication fork stalling. We demonstrate an RNA-DNA helicase activity in UAP56 and that its overexpression suppresses R loops and genome instability induced by depleting 5 different unrelated factors. UAP56/DDX39B localizes to active chromatin and prevents the accumulation of RNA-DNA hybrids over the entire genome. We propose that, in addition to its RNA processing role, UAP56/DDX39B is a key helicase required to eliminate harmful co-transcriptional RNA structures that otherwise would block transcription and replication.
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Project description:The formation of R-loops is a natural consequence of the transcription process, caused by invasion of the DNA duplex by nascent transcripts. These structures have been considered rare transcriptional by-products with potential harmful effects on genome integrity, due to the fragility of the displaced DNA coding strand. However R-loops may also possess beneficial effects as their widespread formation has been detected over CpG island promoters in human genes. Furthermore we have previously shown that R-loops are particularly enriched over G-rich terminator elements. These facilitate RNA polymerase II (Pol II) pausing prior to efficient termination. Here we reveal an unanticipated link between R-loops and RNA interference (RNAi)-dependent H3K9me2 formation over pause site termination regions of mammalian protein coding genes. We show that R-loops induce antisense transcription over these pause elements which in turn lead to the generation of double-strand RNA (dsRNA) and recruitment of Dicer, Ago1, Ago2, and G9a histone lysine methyltransferase (HKMT). Consequently an H3K9me2 repressive mark is formed and Heterochromatin Protein 1γ (HP1γ) is recruited, that reinforces Pol II pausing prior to efficient transcriptional termination. We predict that R-loops promote a chromatin architecture that defines the termination region for a substantial subset of mammalian genes. PolIIS2ph ChIP-seq and input in untreated condition and treated with BIX and RNaseH1 overexpression in HeLa cells. The 4 samples have been multiplexed, pooled and sequenced on 3 lanes of Illumina HiSeq2000.
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2017-11-20 | E-MTAB-5345 | biostudies-arrayexpress
Project description:UAP56/DDX39b is a major co-transcriptional RNA-DNA helicase that unwinds harmful R loops genome-wide
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Project description:R-loops, which consist of a DNA-RNA hybrid and a displaced DNA strand, are known to threaten genome integrity. To counteract this, different mechanisms suppress R-loop accumulation by either preventing the hybridization of RNA with the DNA template (RNA biogenesis factors), unwinding the hybrid (DNA-RNA helicases), or degrading the RNA moiety of the R-loop (type H ribonucleases [RNases H]). Thus far, RNases H are the only nucleases known to cleave DNA-RNA hybrids. Now, we show that the RNase DICER also resolves R-loops. Biochemical analysis reveals that DICER acts by specifically cleaving the RNA within R-loops. Importantly, a DICER RNase mutant impaired in R-loop processing causes a strong accumulation of R-loops in cells. Our results thus not only reveal a function of DICER as an R-loop resolvase independent of DROSHA but also provide evidence for the role of multi-functional RNA processing factors in the maintenance of genome integrity in higher eukaryotes.
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