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Topoisomerase 1 prevents replication stress at R-loop-enriched transcription termination sites

ABSTRACT: Topoisomerase 1 prevents replication stress at R-loop-enriched transcription termination sites

PROVIDER: PRJNA422724 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR11851373.fastq.gz	Fastqsanger.gz
	SRR11851374.fastq.gz	Fastqsanger.gz
	SRR6491520.fastq.gz	Fastqsanger.gz
	SRR6491530.fastq.gz	Fastqsanger.gz
	SRR6491540.fastq.gz	Fastqsanger.gz

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Topoisomerase 1 prevents replication stress at R-loop-enriched transcription termination sites

Project description:R-loops have both positive and negative impacts on chromosome functions. To identify toxic R-loops in the human genome, we have mapped RNA:DNA hybrids, replication stress markers and DNA double strand breaks (DSBs) in cells depleted for Topoisomerase I (Top1), an enzyme that relaxes DNA supercoiling and prevents R-loop formation. RNA:DNA hybrids were found at both promoters (TSS) and terminators (TTS) of highly expressed genes. In contrast, the phosphorylation of RPA by ATR was only detected at TTS, which are preferentially replicated in a head-on orientation relative to the direction of transcription. In Top1-depleted cells, DSBs also cumulated at TTS, leading to persistent checkpoint activation, spreading of -H2AX on chromatin and global replication fork slowdown. 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.

2020-06-20 | GSE108172 | GEO

Topoisomerase 1 prevents replication stress at R-loop-enriched transcription termination sites.

Project description:R-loops have both positive and negative impacts on chromosome functions. To identify toxic R-loops in the human genome, here, we map RNA:DNA hybrids, replication stress markers and DNA double-strand breaks (DSBs) in cells depleted for Topoisomerase I (Top1), an enzyme that relaxes DNA supercoiling and prevents R-loop formation. RNA:DNA hybrids are found at both promoters (TSS) and terminators (TTS) of highly expressed genes. In contrast, the phosphorylation of RPA by ATR is only detected at TTS, which are preferentially replicated in a head-on orientation relative to the direction of transcription. In Top1-depleted cells, DSBs also accumulate at TTS, leading to persistent checkpoint activation, spreading of γ-H2AX on chromatin and global replication fork slowdown. 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.

| S-EPMC7414224 | biostudies-literature

ZFP281-BRCA2 prevents R-loop accumulation during DNA replication

Project description:ZFP281-BRCA2 prevents R-loop accumulation during DNA replication

| PRJNA524627 | ENA

DNA Topoisomerase I differentially modulates R loop across long genes and at human replication origins

Project description:Co-transcriptional R-loops are abundant non-B DNA structures in mammalian genomes. DNA Topoisomerase I (Top1) is often thought to regulate R-loop formation owing to its ability to resolve both positive and negative supercoils. How Top1 regulates R-loop structures at a global level is unknown. Here, we performed high-resolution strand-specific R-loop mapping in human cells depleted for Top1 and found that Top1 depletion resulted in both R-loop gains and losses at thousands of transcribed loci, delineating two distinct gene classes. R-loop gains were characteristic for long, highly transcribed, genes located in gene-poor regions anchored to Lamin B1 domains and in proximity to H3K9me3-marked heterochromatic patches. R-loop losses, by contrast, occurred in gene-rich regions overlapping H3K27me3-marked active replication origins. Interestingly, Top1 depletion coincided with a block of the cell cycle in G0/G1 phase and a trend towards global replication delay. Our findings reveal new properties of Top1 in regulating R-loop homeostasis and suggest a potential role for Top1 in controlling replication origin via R-loop formation.

2018-06-26 | GSE102474 | GEO

Replication termination is mediated by Top2 and occurs at genomic loci containing pausing elements

Project description:[original title] Chromosome replication initiates at multiple replicons and terminates when forks converge. In Escherichia coli, the Tus-TER complex mediates polar fork converging at the terminator region and aberrant termination events challenge chromosome integrity and segregation. Since in eukaryotes termination is less characterized, we used budding yeast to identify the factors assisting fork fusion at replicating chromosomes. Using genomic and mechanistic studies we have identified and characterized 71 chromosomal termination regions (TERs). TERs contain fork pausing elements that influence fork progression and merging. The Rrm3 DNA helicase assists fork progression across TERs counteracting the accumulation of X-shaped structures. The Top2 DNA topoisomerase associates at TERs in S-phase and G2/M facilitates fork fusion and prevents DNA breaks and genome rearrangements at TERs. We propose that in eukaryotes replication fork barriers, Rrm3 and Top2 coordinate replication fork progression and fusion at termination regions thus counteracting abnormal genomic transitions. Signal tracks in BED format suitable for visualization on the UCSC genome browser can be found at http://bio.ifom-ieo-campus.it/supplementary/Fachinetti_et_al_MOLCELL_2010

2010-08-28 | GSE19061 | GEO

Topoisomerase 1 dependent R-loop deficiency drives accelerated replication and genomic instability

Project description:Topoisomerase 1 dependent R-loop deficiency drives accelerated replication and genomic instability

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Topoisomerase 1 dependent R-loop deficiency drives accelerated replication and genomic instability

Project description:DNA replication is a complex process tightly regulated to ensure faithful genome duplication, and its perturbation leads to DNA damage and genomic instability. Replication stress is commonly associated with slow and stalled replication forks. Recently, accelerated replication has emerged as a non-canonical form of replication stress. However, the molecular basis underlying fork acceleration is largely unknown. Here we show that mutated HRAS activation leads to increased topoisomerase 1 (TOP1) expression leading to aberrant replication fork acceleration and DNA damage by decreasing RNA-DNA hybrids or R-loops. In these cells, restoration of TOP1 expression or mild replication inhibition rescues the perturbed replication and reduces DNA damage. Furthermore, TOP1 or RNaseH1 overexpression induces accelerated replication and DNA damage, highlighting the importance of TOP1 equilibrium in regulating R-loop homeostasis to ensure faithful DNA replication and genome integrity. Altogether, our results reveal a novel mechanism of oncogene-induced DNA damage induced by aberrant replication fork acceleration.

2022-09-08 | GSE168738 | GEO

m6A facilitates transcription termination by promoting R-loop formation

Project description:m6A facilitates transcription termination by promoting R-loop formation

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R-loop dependent promoter-proximal termination ensures genome stability

Project description:R-loop dependent promoter-proximal termination ensures genome stability

| PRJNA929274 | ENA

ZFP281-BRCA2 prevents R-loop accumulation during DNA replication

Project description:R-loops are prevalent in mammalian genomes and involved in many fundamental cellular processes. Depletion of BRCA2 leads to aberrant R-loop accumulation, contributing to genome instability. Here, we show that ZFP281 cooperates with BRCA2 in preventing R-loop accumulation to facilitate DNA replication in embryonic stem cells. Mechanistically, we demonstrate that ZFP281 can interact with BRCA2, and that BRCA2 is enriched at G/C-rich promoters and requires both ZFP281 and PRC2 for its proper recruitment to the bivalent chromatin at the genome-wide scale. Furthermore, depletion of ZFP281 or BRCA2 leads to accumulation of R-loops over the bivalent regions, and compromises activation of the developmental genes by retinoic acid during stem cell differentiation. In summary, our results reveal that ZFP281 recruits BRCA2 to the bivalent chromatin regions to ensure proper progression of DNA replication through preventing persistent R-loops.

2022-05-31 | GSE127262 | GEO

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