RTEL1 regulates G4/R-loops to avert replication-transcription collisions
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ABSTRACT:
PROVIDER: PRJNA678867 | ENA |
REPOSITORIES: ENA
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Project description:RNAPII is mainly responsible for mRNA transcription and plays a vital role in gene expression. In light of the above results showing that cellular G4s are highly correlated with RNAPII-mediated DNA loops, we performed the RNA-seq to evaluate how G4-dependent long-range DNA interactions modulate gene expression. We revealed that PDS treatment modulates the expression of not only genes with G4 in their promoters, but also those with promoters being connected with distal G4 through RNAPII-linked long-range DNA interactions.
2023-09-13 | GSE222207 | GEO
Project description:The goal of this study is to compare the transcription profile of mouse embryonic fibroblasts upon deletion of the helicase RTEL1 and stabilisation of G-quadruplexes (G4) with the G4 stabilisation drug TMPyP4.
2021-01-04 | GSE149850 | GEO
Project description:In metazoans, the largest sirtuin, SIRT1, is a nuclear protein implicated in epigenetic modifications, circadian signaling, DNA recombination, replication and repair. Our previous studies have demonstrated that SIRT1 binds replication origins and inhibits replication initiation from a group of potential initiation sites (dormant origins). We studied the effects of aging and SIRT1 activity on replication origin usage and the incidence of transcription-replication collisions (creating R-loop structures) in adult human cells obtained at different time points during chronological aging and in cancer cells. In primary, untransformed cells, SIRT1 activity declined, and the prevalence of R-loops rose with chronological aging. Both the reduction of SIRT1 activity and the increased abundance of R-loops were also observed during the passage of primary cells in culture. All cells, regardless of donor age or transformation status, reacted to short-term, acute chemical inhibition of SIRT1 with the activation of excessive replication initiation events coincident with an increased prevalence of R-loops. However, only cancer cells showed genome-wide activation of dormant origins during long-term proliferation with mutated or depleted SIRT1, whereas in primary cells, aging-associated SIRT1-mediated activation of dormant origins was restricted to rDNA loci. These observations suggest that chronological aging and the associated decline in SIRT1 activity relaxes the regulatory networks that protect cells against excess replication and that the mechanisms protecting from replication-transcription collisions at the rDNA loci manifest as a differentially enhanced sensitivity to SIRT1 decline and chronological aging.
2023-11-27 | GSE247469 | GEO
Project description:R loops are an important source of genome instability largely due to its negative impact on replication progression. Yra1/ALY is an abundant RNA-binding factor conserved from yeast to humans and required for mRNA export, but its excess cause lethality and genome instability. Here, we show that Yra1 binds RNA-DNA hybrids in vitro and when artificially overexpressed is recruited to chromatin in an RNA-DNA hybrid-dependent manner stabilizing R loops and converting them into replication obstacles in vivo. Importantly, excess of Yra1 increases R loop-mediated genome instability caused by transcription-replication collisions regardless of whether they are co-directional or head-on. It also induces telomere shortening and senescence, consistent with a defect in telomere replication. Our results indicate that R loops form transiently in cells regardless of replication and, after stabilization by excess Yra1, they compromise genome integrity, in agreement with a two-step model of R loop-mediated genome instability. This work opens new perspectives to understand transcription-associated genome instability in repair-deficient cells, including tumoral cells.
2018-06-27 | GSE113580 | GEO
Project description:Yra1-bound R loops cause orientation-independent transcription-replication collisions and telomere instability
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Project description:Regulator of telomere length 1 (RTEL1) is an essential helicase that maintains telomere integrity and facilitates DNA replication. The source of replication stress in Rtel1-deficient cells remains unclear. Here, we report that loss of RTEL1 confers extensive transcriptional changes independent of its roles at telomeres. The majority of affected genes in Rtel1-/- cells possess G-quadruplex (G4)-DNA-forming sequences in their promoters and are similarly altered at a transcriptional level in wild-type cells treated with the G4-DNA stabilizer TMPyP4 (5,10,15,20-Tetrakis-(N-methyl-4-pyridyl)porphine). Failure to resolve G4-DNAs formed in the displaced strand of RNA-DNA hybrids in Rtel1-/- cells is suggested by increased R-loops and elevated transcription-replication collisions (TRCs). Moreover, removal of R-loops by RNaseH1 overexpression suppresses TRCs and alleviates the global replication defects observed in Rtel1-/- and Rtel1PIP_box knockin cells and in wild-type cells treated with TMPyP4. We propose that RTEL1 unwinds G4-DNA/R-loops to avert TRCs, which is important to prevent global deregulation in both transcription and DNA replication.
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Project description:Genome-wide characterisation of replication and transcription programs upon G4-stabilisation by PhenDC3
2019-06-01 | GSE126477 | GEO
Project description:Here, we identify that a human DNA helicase RTEL1, which is known to play a role in the maintenance of telomeres by interacting with proteins in the shelterin complex by resolving G4 quadruplexes, is essential for prevention of R-loop accumulation during replication and for MiDAS in mitosis at both CFSs and telomeres. Our findings indicate that RTEL1 plays a genome-wide role in preventing the collapse of replication forks at sites of G-quadruplexes and R-loop formation. Considering cancer cells rely on RTEL1 function to resolve the elevated transcription-replication conflicts caused by oncogene activation, RTEL1 is a potential drug target for cancer therapy.
2020-02-12 | GSE129907 | GEO
Project description:Regions of DNA with the potential to form secondary structure pose a frequent and significant impediment to DNA replication that must be actively countered by cells in order to preserve genetic and epigenetic integrity. The fork protection complex (FPC), a conserved group of replisome-associated proteins, comprising Timeless, plays an important role in maintaining efficient replisome function. A previously unappreciated DNA binding domain in the C terminus of Timeless, which exhibits specificity towards G4 structures, acts in collaboration with the DDX11 helicase to ensure replication of G4 structures in vivo and maintenance of genetic and epigenetic stability. Using RNA-seq experiments, we show that (i) Timeless and DDX11 share common gene targets, (ii) the promoter of Timeless- and DDX11-dependent genes are enriched in G4 structures in the vicinity of their promoter and (iii) both Timeless and DDX11 share a common set of gene targets with the FANCJ helicase known to maintain epigenetic stability in the vicinity of G4 structures.
2020-07-01 | GSE139256 | GEO
Project description:Collisions of the transcription and replication machineries on the same DNA strand can pose a significant threat to genomic stability. These collisions occur in part due to the formation of RNA-DNA hybrids termed R-loops, in which a newly transcribed RNA molecule hybridizes with the DNA template strand. This study investigated the role of RAD52, a known DNA repair factor, in preventing collisions by directing R-loop formation and resolution. We show that RAD52 deficiency increases R-loop accumulation, exacerbating collisions and resulting in elevated DNA damage. Furthermore, RAD52's ability to interact with the transcription machinery, coupled with its capacity to facilitate R-loop dissolution, highlights its role in preventing collisions. Lastly, we provide evidence of an increased mutational burden from double-strand breaks at conserved R-loop sites in human tumor samples, which is increased in tumors with low RAD52 expression. In summary, this study underscores the importance of RAD52 in orchestrating the balance between replication and transcription processes to prevent collisions and maintain genome stability.
2024-08-25 | PXD054611 | Pride