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ZFP281-BRCA2 prevents R-loop accumulation during DNA replication

ABSTRACT: ZFP281-BRCA2 prevents R-loop accumulation during DNA replication

PROVIDER: PRJNA524627 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR19409778_1.fastq.gz	Fastqsanger.gz
	SRR19409778_2.fastq.gz	Fastqsanger.gz
	SRR19409779_1.fastq.gz	Fastqsanger.gz
	SRR19409779_2.fastq.gz	Fastqsanger.gz
	SRR19409780_1.fastq.gz	Fastqsanger.gz

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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

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. ZFP281 depletion reduces PCNA levels on chromatin and impairs DNA replication. 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.

| S-EPMC9205938 | biostudies-literature

Linker histone H1 prevents R-loop accumulation and genome instability in heterochromatin

Project description:Linker histone H1 prevents R-loop accumulation and genome instability in heterochromatin

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

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

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Elongation Factor TFIIS Prevents Transcription Stress and R-Loop Accumulation to Maintain Genome Stability [TT-seq]

Project description:Elongation Factor TFIIS Prevents Transcription Stress and R-Loop Accumulation to Maintain Genome Stability [TT-seq]

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Elongation Factor TFIIS Prevents Transcription Stress and R-Loop Accumulation to Maintain Genome Stability [ChIP-seq]

Project description:Elongation Factor TFIIS Prevents Transcription Stress and R-Loop Accumulation to Maintain Genome Stability [ChIP-seq]

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Elongation Factor TFIIS Prevents Transcription Stress and R-Loop Accumulation to Maintain Genome Stability [ RNA-seq]

Project description:Elongation Factor TFIIS Prevents Transcription Stress and R-Loop Accumulation to Maintain Genome Stability [ RNA-seq]

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MiDAS in BRCA2-deficient cells originate at early S-phase transcription-replication conflicts

Project description:Multiple replication abnormalities cause cells lacking BRCA2 to enter mitosis with under-replicated DNA and to activate mitotic DNA synthesis (MiDAS). However, the precise position of these MiDAS sites, as well as their origin, remains unknown. Here we labelled mitotic nascent DNA and performed high-throughput sequencing to identify at high-resolution the sites where MiDAS occurs in the absence of BRCA2. This approach revealed 150 genomic loci affected by MiDAS, which map within regions replicating during early S-phase and are therefore distinct from the aphidicolin-induced common fragile sites. Moreover, these sites largely localise near early firing origins and within genes transcribed in early S, suggesting that they stem from transcription-replication conflicts (TCRs). Inhibiting transcription with 5,6-dichloro-1-β-D-ribofuranosylbenzimidazole (DRB) during early S-phase abrogates MiDAS. Strikingly, MiDAS sites co-localise with genomic loci where R-loops form in unchallenged conditions, suggesting that R-loop accumulation caused by BRCA2 inactivation leads to DNA lesion which are repaired by MiDAS. RAD52 is required in this process, as its abrogation in BRCA2-deficient cells reduces the rate of MiDAS and causes DNA damage accumulation in G1. Furthermore, MiDAS sites triggered by BRCA2 inactivation are hotspots for genomic rearrangement in BRCA2-mutated breast tumours. These results indicate that BRCA2 acts in early S-phase to protect TRC- and R-loop-induced DNA lesions, thereby preventing them from becoming a source of genomic instability and tumorigenesis.

2022-08-01 | GSE196163 | GEO

ZFP281 coordinates DNMT3 and TET1 in pluripotent state transitions [STEM-seq]

Project description:The progression and transition between the naïve, formative, and primed pluripotent states are accompanied by a sharp activation of the de novo DNA methyltransferases and the reorganization of transcriptional and epigenetic landscapes. Here we identified Zinc Finger Protein 281 (ZFP281) as an essential factor in the formative-to-primed pluripotent state transition. Using a knockout mouse model and a knockin degron cell system, we revealed that transcription of Dnmt3a/3b depends on the activity of ZFP281 in embryonic stem cells, epiblast-like cells, and epiblast stem cells. Mechanically, chromatin-bound ZFP281 and DNA hydroxylase TET1 are decreased in the formative state but recovered in the primed state to compete with DNMT3A/3B for establishing the DNA methylation and gene expression programs of primed pluripotency. In addition, chromatin occupancy of ZFP281 and TET1 depend on the R-loop structures formed at the ZFP281 target gene promoters devoid of DNA methylation. Our study demonstrates a comprehensive role of ZFP281 in modulating DNA methylation and demethylation for the establishment and maintenance of primed pluripotency.

2023-12-14 | GSE227093 | GEO