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

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

PROVIDER: PRJNA803497 | ENA |

REPOSITORIES: ENA

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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

BRCA2 suppresses “head-on” transcription-replication conflicts incurred by dormant origin firing at transcription termination sites [RNA-seq]

Project description:BRCA2 is a tumor suppressor protein responsible for safeguarding the cellular genome from genotoxicity and replication stress, but the mechanism(s) by which this is achieved remains elusive. Here, we provide evidence that BRCA2 acts as a critical suppressor of “head-on” transcription-replication conflicts (HO-TRCs). Using Okazaki-fragment sequencing (Ok-seq) and computational analysis, we identified new origins (dormant origins) that are activated near the transcription termination sites (TTS) of highly expressed, long genes in response to replication stress. Dormant origins are a source for HO-TRCs, and drug treatments that inhibit dormant origin firing led to a reduction in HO-TRCs, R-loop formation, and DNA damage. Using super-resolution microscopy, we showed that HO-TRC events track with elongating RNA polymerase II, but not with transcription initiation. Importantly, RNaseH2 is recruited to sites of HO-TRCs in a BRCA2-dependent manner to help alleviate toxic R-loops associated with HO-TRCs. Collectively, our results identify a new source of genomic instability caused by HO-TRCs in BRCA2-deficient ovarian cancer precursor cells, providing a new strategy in modulating HO-TRCs to enhance genomic instability

2024-03-28 | GSE239857 | GEO

BRCA2 suppresses “head-on” transcription-replication conflicts incurred by dormant origin firing at transcription termination sites [Ok-seq]

2024-03-28 | GSE239856 | GEO

Transcription-Replication Conflicts drive the Synthetic Lethality of PARP Inhibitors with BRCA2-Deficiency

Project description:Transcription-Replication Conflicts drive the Synthetic Lethality of PARP Inhibitors with BRCA2-Deficiency

| PRJNA909256 | ENA

BRCA2 suppresses “head-on” transcription-replication conflicts incurred by dormant origin firing at transcription termination sites

Project description:BRCA2 suppresses “head-on” transcription-replication conflicts incurred by dormant origin firing at transcription termination sites

| PRJNA1001273 | ENA

Midas v5

Project description:Midas genome assembly version 5

| PRJEB6974 | 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

Atypical mitotic DNA synthesis sequencing (MiDAS-seq) in U2OS cells depleted for RAD51

Project description:DNA replication stress is an established driver of cancer-associated chromosomal rearrangements. Replication stress perturbs the duplication of late-replicating loci and activates a mitotic DNA repair pathway (termed MiDAS) for completion of replication. We here investigated RAD51-independent MiDAS.

2022-06-27 | GSE196278 | GEO

BRCA2 suppresses “head-on” transcription-replication conflicts incurred by dormant origin firing at transcription termination sites [RNA-seq]

Project description:BRCA2 suppresses “head-on” transcription-replication conflicts incurred by dormant origin firing at transcription termination sites [RNA-seq]

| PRJNA1001277 | ENA

BRCA2 suppresses “head-on” transcription-replication conflicts incurred by dormant origin firing at transcription termination sites [Ok-seq]

Project description:BRCA2 suppresses “head-on” transcription-replication conflicts incurred by dormant origin firing at transcription termination sites [Ok-seq]

| PRJNA1001276 | ENA

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