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Transcription–replication conflicts underlie sensitivity to PARP inhibitors

ABSTRACT: Transcription–replication conflicts underlie sensitivity to PARP inhibitors

PROVIDER: PRJNA909256 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR22548720.fastq.gz	Fastqsanger.gz
	SRR22548721.fastq.gz	Fastqsanger.gz
	SRR22548722.fastq.gz	Fastqsanger.gz
	SRR22548723.fastq.gz	Fastqsanger.gz
	SRR25339400.fastq.gz	Fastqsanger.gz

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Transcription-replication conflicts underlie sensitivity to PARP inhibitors.

Project description:An important advance in cancer therapy has been the development of poly(ADP-ribose) polymerase (PARP) inhibitors for the treatment of homologous recombination (HR)-deficient cancers1-6. PARP inhibitors trap PARPs on DNA. The trapped PARPs are thought to block replisome progression, leading to formation of DNA double-strand breaks that require HR for repair7. Here we show that PARP1 functions together with TIMELESS and TIPIN to protect the replisome in early S phase from transcription-replication conflicts. Furthermore, the synthetic lethality of PARP inhibitors with HR deficiency is due to an inability to repair DNA damage caused by transcription-replication conflicts, rather than by trapped PARPs. Along these lines, inhibiting transcription elongation in early S phase rendered HR-deficient cells resistant to PARP inhibitors and depleting PARP1 by small-interfering RNA was synthetic lethal with HR deficiency. Thus, inhibiting PARP1 enzymatic activity may suffice for treatment efficacy in HR-deficient settings.

| S-EPMC11006605 | biostudies-literature

Transcription–replication conflicts underlie sensitivity to PARP inhibitors

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

TET2 and DNMT3A Mutations Exert Divergent Effects on DNA Repair and Sensitivity of Leukemia Cells to PARP Inhibitors

Project description:TET2 and DNMT3A regulate the sensitivity to PARP inhibitor

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MND1 and PSMC3IP control PARP inhibitor sensitivity in mitotic cells

Project description:MND1 and PSMC3IP control PARP inhibitor sensitivity in mitotic cells

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Deletion of 11q in neuroblastomas drives sensitivity to PARP inhibition

Project description:Deletion of 11q in neuroblastomas drives sensitivity to PARP inhibition

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Combinatorial treatment with PARP and MAPK inhibitors overcomes phenotype switch-driven drug resistance in advanced melanoma

Project description:Metastatic melanoma is either intrinsically resistant or rapidly acquires resistance to targeted therapy treatments, such as MAPK inhibitors. A leading cause of resistance to targeted therapy is a dynamic transition of melanoma cells from a proliferative to a highly invasive state, a phenomenon called phenotype switching. Mechanisms regulating phenotype switching represent potential targets for improving treatment of melanoma patients. Using a drug screen targeting chromatin regulators in patient-derived 3D MAPK inhibitor-resistant melanoma cell cultures, we discovered that PARP inhibitors restore sensitivity to MAPK inhibitors, independent of DNA damage repair pathways. Integrated transcriptomic, proteomic, and epigenomic analyses demonstrated that PARP inhibitors induce lysosomal autophagic cell death, accompanied by enhanced mitochondrial lipid metabolism that ultimately increases antigen presentation and sensitivity to T-cell cytotoxicity. Moreover, transcriptomic and epigenetic rearrangements induced by PARP inhibition reversed EMT-like phenotype switching, which redirected melanoma cells toward a proliferative and MAPK inhibitor-sensitive state. The combination of PARP and MAPK inhibitors synergistically induced cancer cell death both in vitro and in vivo in patient-derived xenograft models. Therefore, this study provides a scientific rationale for treating melanoma patients with PARP inhibitors in combination with MAPK inhibitors to abrogate acquired therapy resistance.

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The MYCN oncoprotein resolves conflicts of stalling RNA Polymerase with the replication fork [DP_EXOSC10_Screen]

Project description:During the S-phase, conflicts of replication forks with RNA Polymerase II (RNAPII) threaten genomic stability. While the PAF complex can resolve such conflicts during elongation, the particularly deleterious conflicts with stalling RNAPII are resolved by an as of yet unknown mechanism. Here we show that the MYCN oncoprotein forms a ternary complex with RNAPII and the nuclear RNA exosome, a 3’‑5’ exoribonuclease complex. Together with TFIIS, this complex restarts promoter‑proximal RNAPII, allows escape from co-directional transcription-replication conflicts and prevents double‑strand break accumulation. In cells lacking RNA exosome function, MYCN globally terminates transcription. MYCN-mediated termination is triggered by ATM‑dependent recruitment of BRCA1, which then stabilizes nuclear mRNA decapping complexes. Disruption of mRNA decapping activates ATR, indicative of head-on transcription-replication conflicts, and inhibits DNA replication. We propose that MYCN resolves transcription-replication conflicts via this two-step mechanism to sustain the rapid proliferation of neuroendocrine tumor cells.

2021-12-10 | GSE164568 | GEO

The MYCN oncoprotein resolves conflicts of stalling RNA Polymerase with the replication fork [DP_EXOSC10_BLISS]

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The MYCN oncoprotein resolves conflicts of stalling RNA Polymerase with the replication fork [DP_EXOSC10_ChIP_4sUseq]

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Pharmacological depletion of RNA splicing factor RBM39 by indisulam synergizes with PARP inhibitors in high-grade serous ovarian carcinoma

Project description:Ovarian high-grade serous carcinoma (HGSC) is the most common and lethal subtype of ovarian cancer with limited therapeutic options. In recent years, PARP inhibitors have demonstrated significant clinical benefits, especially in patients with BRCA1/2 mutations. However, acquired drug resistance and relapse is a major challenge. Therapies disrupting the spliceosome alter cancer transcriptomes and have shown potential to improve PARP inhibitor response. Indisulam (E7070) has been identified as a molecular glue that brings splicing factor RBM39 and DCAF15 E3 ubiquitin ligase in close proximity. Exposure to indisulam induces RBM39 proteasomal degradation through DCAF15-mediated polyubiquitination and subsequent RNA splicing defects. In this study, we demonstrate that loss of RBM39 induces splicing errors in DNA damage repair genes in ovarian cancer, leading to increased sensitivity to PARP inhibitors such as olaparib. Indisulam synergized with olaparib in multiple in vitro models of ovarian cancer regardless of PARP inhibitor sensitivity and improved olaparib response in mice bearing PARP inhibitor-resistant tumors. DCAF15 expression, but not BRCA1/2 mutational status, was essential for the synergy between indisulam and olaparib, suggesting that the combination therapy may benefit patients irrespective of their BRCA1/2 status. These findings demonstrate that combining RBM39 degraders and PARP inhibitors is a promising therapeutic approach to improving PARP inhibitor response in ovarian HGSC

2023-01-22 | GSE223011 | GEO

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