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

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE239858 | GEO | 2024/03/27

REPOSITORIES: GEO

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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

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

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

ATR-mediated phosphorylation of FANCI regulates dormant origin firing in response to replication stress.

Project description:Excess dormant origins bound by the minichromosome maintenance (MCM) replicative helicase complex play a critical role in preventing replication stress, chromosome instability, and tumorigenesis. In response to DNA damage, replicating cells must coordinate DNA repair and dormant origin firing to ensure complete and timely replication of the genome; how cells regulate this process remains elusive. Herein, we identify a member of the Fanconi anemia (FA) DNA repair pathway, FANCI, as a key effector of dormant origin firing in response to replication stress. Cells lacking FANCI have reduced number of origins, increased inter-origin distances, and slowed proliferation rates. Intriguingly, ATR-mediated FANCI phosphorylation inhibits dormant origin firing while promoting replication fork restart/DNA repair. Using super-resolution microscopy, we show that FANCI co-localizes with MCM-bound chromatin in response to replication stress. These data reveal a unique role for FANCI as a modulator of dormant origin firing and link timely genome replication to DNA repair.

| S-EPMC4408929 | biostudies-literature

Mitotic DNA synthesis is caused by transcription-replication conflicts in BRCA2-deficient cells.

Project description:Aberrant replication causes cells lacking BRCA2 to enter mitosis with under-replicated DNA, which activates a repair mechanism known as mitotic DNA synthesis (MiDAS). Here, we identify genome-wide the sites where MiDAS reactions occur when BRCA2 is abrogated. High-resolution profiling revealed that these sites are different from MiDAS at aphidicolin-induced common fragile sites in that they map to genomic regions replicating in the early S-phase, which are close to early-firing replication origins, are highly transcribed, and display R-loop-forming potential. Both transcription inhibition in early S-phase and RNaseH1 overexpression reduced MiDAS in BRCA2-deficient cells, indicating that transcription-replication conflicts (TRCs) and R-loops are the source of MiDAS. Importantly, the MiDAS sites identified in BRCA2-deficient cells also represent hotspots for genomic rearrangements in BRCA2-mutated breast tumors. Thus, our work provides a mechanism for how tumor-predisposing BRCA2 inactivation links transcription-induced DNA damage with mitotic DNA repair to fuel the genomic instability characteristic of cancer cells.

| S-EPMC9631240 | biostudies-literature

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

Project description:To examine replication fork progression firing upon TIMELESS/TIPIN knockdown, EdUseq was performed in HeLa cells transfected with siCTRL, siTIMELESS or siTIPIN, synchronised with Thymidine and then released for 120 min in S phase, with the last 30 minutes being labeled with EdU.

2024-04-12 | GSE220223 | GEO

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

MTBP phosphorylation controls DNA replication origin firing.

Project description:Faithful genome duplication requires regulation of origin firing to determine loci, timing and efficiency of replisome generation. Established kinase targets for eukaryotic origin firing regulation are the Mcm2-7 helicase, Sld3/Treslin/TICRR and Sld2/RecQL4. We report that metazoan Sld7, MTBP (Mdm2 binding protein), is targeted by at least three kinase pathways. MTBP was phosphorylated at CDK consensus sites by cell cycle cyclin-dependent kinases (CDK) and Cdk8/19-cyclin C. Phospho-mimetic MTBP CDK site mutants, but not non-phosphorylatable mutants, promoted origin firing in human cells. MTBP was also phosphorylated at DNA damage checkpoint kinase consensus sites. Phospho-mimetic mutations at these sites inhibited MTBP's origin firing capability. Whilst expressing a non-phospho MTBP mutant was insufficient to relieve the suppression of origin firing upon DNA damage, the mutant induced a genome-wide increase of origin firing in unperturbed cells. Our work establishes MTBP as a regulation platform of metazoan origin firing.

| S-EPMC7895959 | biostudies-literature

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