Yra1-bound R loops cause orientation-independent transcription-replication collisions and telomere instability
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA453145 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR7059073.fastq.gz | Fastqsanger.gz | |||
| SRR7059074.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 2 of 2 |
Similar Datasets
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:RTEL1 regulates G4/R-loops to avert replication-transcription collisions
| PRJNA678867 | ENA
Project description:R loops are an important source of genome instability, largely due to their 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 causes lethality and genome instability. Here, we show that, in addition to ssDNA and ssRNA, Yra1 binds RNA-DNA hybrids in vitro and, when artificially overexpressed, can be recruited to chromatin in an RNA-DNA hybrid-dependent manner, stabilizing R loops and converting them into replication obstacles in vivo. Importantly, an excess of Yra1 increases R-loop-mediated genome instability caused by transcription-replication collisions regardless of whether they are codirectional or head-on. It also induces telomere shortening in telomerase-negative cells and accelerates senescence, consistent with a defect in telomere replication. Our results indicate that RNA-DNA hybrids form transiently in cells regardless of replication and, after stabilization by excess Yra1, 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.
| S-EPMC6075034 | biostudies-literature
Project description:Here we found that ILF3 prefers to bind telomere R-loops and protects telomere from aberrant homologous recombination. ILF3 knockout induces TERRA aggregation onto telomere and activates telomere DNA damage response (DDR). Furthermore, ILF3 deficiency disrupts telomere homeostasis and induces abnormal ALT-mediated telomere lengthening
2022-03-04 | PXD032093 |
Project description:Telomeres prevent ATM activation by sequestering chromosome termini within telomere loops (t-loops). Mitotic arrest promotes telomere linearity and a localized ATM-dependent telomere DNA damage response (DDR) through an unknown mechanism. Using unbiased interactomics, biochemical screening, molecular biology, and super-resolution imaging, we found that mitotic arrest-dependent (MAD) telomere deprotection requires the combined activities of the Chromosome passenger complex (CPC) on shelterin, and the BLM-TOP3A-RMI1/2 (BTR) complex on t-loops. During mitotic arrest, the CPC component Aurora Kinase B (AURKB) phosphorylated both the TRF1 hinge and TRF2 basic domains. Phosphorylation of the TRF1 hinge domain enhances CPC and TRF1 interaction through the CPC Survivin subunit. Meanwhile, phosphorylation of the TRF2 basic domain promotes telomere linearity, activates a telomere DDR dependent on BTR-mediated double Holliday junction dissolution, and leads to mitotic death. We identify that the TRF2 basic domain functions in mitosis-specific telomere protection and reveal a regulatory role for TRF1 in controlling a physiological ATM-dependent telomere DDR. The data demonstrate that MAD telomere deprotection is a sophisticated active mechanism that exposes telomere ends to signal mitotic stress.
2025-01-28 | PXD043281 | Pride
Project description:Collisions of transcription and replication machinery on the same DNA strand can pose a significant threat to genomic stability. These collision occur in part due to of RNA-DNA hybrids termed R-loops, in which a newly synthesized RNA molecule hybridizes with the DNA template strand. This study investigated the novel role of RAD52, a known DNA repair factor, in preventing collisions by managing R-loop formation and resolution. We show that RAD52 deficiency increases R-loop accumulation, exacerbating collisions and resulting in elevated DNA damage. Further, 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 the first evidence of an increased mutational burden at conserved R-loop sites in human tumor samples. In summary, this study underscores the importance of RAD52 in orchestrating the delicate balance between replication and transcription processes to prevent collisions and maintain genome stability.
2024-07-11 | GSE266483 | GEO
Project description:CCCTC binding factor (CTCF) is an important factor in the maintenance of chromatin chromatin interactions, yet the mechanism regulating its binding to chromatin is unknown. We demonstrate that zinc finger protein 143 (ZNF143) is a key regulator for CTCF bound promoter enhancer loops. In the murine genome, a large percentage of CTCF and ZNF143 DNA binding motifs are distributed 37 bp apart in the convergent orientation. Furthermore, deletion of ZNF143 leads to loss of CTCF binding on promoter and enhancer regions associated with gene expression changes. CTCF bound promoter enhancer loops are also disrupted after excision of ZNF143. ZNF143 CTCF bound promoter enhancer loops regulate gene expression patterns essential for maintenance of murine hematopoietic stem and progenitor cell integrity. Our data suggest a common feature of gene regulation that ZNF143 is a critical factor for CTCF bound promoter enhancer loops.
2020-10-22 | GSE144712 | GEO
Project description:Telomere shortening rates must be regulated to prevent premature replicative senescence. TERRA R-loops become stabilized at critically short telomeres to promote their elongation through homology-directed repair (HDR), thereby counteracting senescence onset. Using a non-bias proteomic approach to identify telomere binding factors, we identified Npl3, an RNA-binding protein previously implicated in multiple RNA biogenesis processes. Using Chromatin- and RNA immunoprecipitation, we demonstrate that Npl3 interacts with TERRA and telomeres. Furthermore, we show that Npl3 associates to telomeres in an R-loop dependent manner, as changes in R-loop levels, e.g. at short telomeres, modulate the recruitment of Npl3 to chromosome ends. Through a series of genetic and biochemical approaches we demonstrate that Npl3 binds to TERRA and stabilizes R-loops at short telomeres, which in turn promotes HDR and prevents premature replicative senescence onset. This may have implications for diseases associated with excessive telomere shortening.
2020-01-31 | PXD016772 | Pride
Project description:Translation of aberrant mRNAs can cause ribosomes to stall, leading to collisions with trailing ribosomes. Collided ribosomes are specifically recognized by ZNF598 to initiate protein and mRNA quality control pathways. Here we found using quantitative proteomics of collided ribosomes that EDF1 is a ZNF598-independent sensor of ribosome collisions. EDF1 recruits and stabilizes GIGYF2 at collisions to inhibit translation initiation in cis via 4EHP. The GIGYF2 axis acts independently of the ZNF598 axis, but each pathway’s output is more pronounced without the other. We propose that the widely conserved and highly abundant EDF1 monitors the transcriptome for excessive ribosome density, then triggers a GIGYF2-mediated response to locally and temporarily reduce ribosome loading. Only when collisions persist is translation abandoned to initiate ZNF598-dependent quality control. This tiered response to ribosome collisions would allow cells to dynamically tune translation rates while ensuring fidelity of the resulting protein products.
2020-07-14 | PXD020239 | Pride
Project description:Transcription is a major obstacle for replication fork progression and a cause of genome instability. Yra1 is an essential nuclear factor of the evolutionarily conserved family of hnRNP-like export factors that when overexpressed impairs mRNA export and cell growth. Through this ChIP-chip analysis it is shown that Yra1 binds to active chromatin and is enriched at telomeres when it is overexpressed, in agreement with a possible role of this mRNP factor in the maintenance of telomere integrity. Our data indicate that YRA1 overexpression correlates with replication impairment as inferred by the increase of Rrm3, a helicase involved in the replication fork progression, at transcribed genes and telomeres. ChIP-chip studies were perfomed with antibodies against HA-tagged Yra1 protein in wild-type cells and cells overexpressing YRA1 of the yeast S. Cerevisiae, as well as Flag-tagged Rrm3 protein in both wild-type and cells overexpressing YRA1.
2016-03-11 | E-GEOD-68486 | biostudies-arrayexpress