M6A facilitates transcription termination by promoting R-loop formation
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA556884 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR9667910_1.fastq.gz | Fastqsanger.gz | |||
| SRR9667910_2.fastq.gz | Fastqsanger.gz | |||
| SRR9667930_1.fastq.gz | Fastqsanger.gz | |||
| SRR9667930_2.fastq.gz | Fastqsanger.gz | |||
| SRR9667940_1.fastq.gz | Fastqsanger.gz |
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Project description:This SuperSeries is composed of the SubSeries listed below.
2019-10-15 | GSE134964 | GEO
Project description:Telomerase-negative tumors can maintain telomere length by alternative lengthening of telomeres (ALT) but the mechanism of telomere maintenance in ALT cells is not well understood. A significant portion of the relapse Neuroblastoma (NB) tumors are positive for ALT which suggests better dissecting the ALT mechanism could provide novel therapeutic opportunities. TERRA RNA which is derived from the telomere ends is localized to telomeres in R-loop dependent manner and is essential for telomere maintenance. In the present study, we provide evidence that RNA modification at the N6 position of internal adenosine (m6A) in TERRA RNA by methyl transferase METTL3 is essential for telomere maintenance in ALT cells and loss of TERRA m6A/METTL3 leads to accumulation of DNA damage over telomere. Our data suggest that m6A modification in TERRA RNA is required for R-loop formation and telomere targeting of TERRA. We observed that R-loop enriched TERRA is abundantly m6A modified and m6A mediated recruitment of hnRNPA2B1 to TERRA RNA is essential for R-loop formation. Together our study suggests that m6A-mediated R-loop formation could be a widespread mechanism utilized by other chromatin-interacting lncRNAs. We also show treating ALT positive NB cells with small molecule METTL3 inhibitor leads to compromised telomere targeting of TERRA and accumulation of DNA damage over telomere, suggesting METTL3 inhibition could be a therapeutic opportunity for ALT positive NB.
2023-12-13 | GSE240690 | GEO
Project description:Telomerase-negative tumors can maintain telomere length by alternative lengthening of telomeres (ALT) but the mechanism of telomere maintenance in ALT cells is not well understood. A significant portion of the relapse Neuroblastoma (NB) tumors are positive for ALT which suggests better dissecting the ALT mechanism could provide novel therapeutic opportunities. TERRA RNA which is derived from the telomere ends is localized to telomeres in R-loop dependent manner and is essential for telomere maintenance. In the present study, we provide evidence that RNA modification at the N6 position of internal adenosine (m6A) in TERRA RNA by methyl transferase METTL3 is essential for telomere maintenance in ALT cells and loss of TERRA m6A/METTL3 leads to accumulation of DNA damage over telomere. Our data suggest that m6A modification in TERRA RNA is required for R-loop formation and telomere targeting of TERRA. We observed that R-loop enriched TERRA is abundantly m6A modified and m6A mediated recruitment of hnRNPA2B1 to TERRA RNA is essential for R-loop formation. Together our study suggests that m6A-mediated R-loop formation could be a widespread mechanism utilized by other chromatin-interacting lncRNAs. We also show treating ALT positive NB cells with small molecule METTL3 inhibitor leads to compromised telomere targeting of TERRA and accumulation of DNA damage over telomere, suggesting METTL3 inhibition could be a therapeutic opportunity for ALT positive NB.
2023-12-13 | GSE219212 | GEO
Project description:Telomerase-negative tumors can maintain telomere length by alternative lengthening of telomeres (ALT) but the mechanism of telomere maintenance in ALT cells is not well understood. A significant portion of the relapse Neuroblastoma (NB) tumors are positive for ALT which suggests better dissecting the ALT mechanism could provide novel therapeutic opportunities. TERRA RNA which is derived from the telomere ends is localized to telomeres in R-loop dependent manner and is essential for telomere maintenance. In the present study, we provide evidence that RNA modification at the N6 position of internal adenosine (m6A) in TERRA RNA by methyl transferase METTL3 is essential for telomere maintenance in ALT cells and loss of TERRA m6A/METTL3 leads to accumulation of DNA damage over telomere. Our data suggest that m6A modification in TERRA RNA is required for R-loop formation and telomere targeting of TERRA. We observed that R-loop enriched TERRA is abundantly m6A modified and m6A mediated recruitment of hnRNPA2B1 to TERRA RNA is essential for R-loop formation. Together our study suggests that m6A-mediated R-loop formation could be a widespread mechanism utilized by other chromatin-interacting lncRNAs. We also show treating ALT positive NB cells with small molecule METTL3 inhibitor leads to compromised telomere targeting of TERRA and accumulation of DNA damage over telomere, suggesting METTL3 inhibition could be a therapeutic opportunity for ALT positive NB.
2023-12-13 | GSE219146 | GEO
Project description:Base J and H3.V promote RNA Polymerase (RNAP) II termination within polycistronic gene clusters in the kinetoplastid species Trypanosoma brucei. Although base J has been shown to promote RNAP II termination in the related kinetoplastid species Leishmania major and Leishmania tarentolae, the role of H3.V was unclear. The effect of acute J loss on mRNA transcript abundance was also unknown. We find here that H3.V does not promote transcription termination in Leishmania major, but loss of H3.V does reduce J levels. The J loss in H3.V knockout cells is not enough to result in a termination defect, which we show is due to a threshold level of J that is sufficient to promote termination. Loss of J beyond that threshold results in termination defects. Further, the decreased J in H3.V knockout cells allowed greater reduction of J by dimethyloxalylglycine (DMOG), which inhibits J synthesis, compared to wild type cells treated with DMOG, and resulted in stronger defects in RNAP II termination and cell growth. By mRNA-seq we see largely upregulation of genes near the ends of gene clusters following J loss, indicating that J represses genes near termination sites. These findings reveal a conserved role of J in promoting termination prior to the end of polycistronic gene clusters in kinetoplastid parasites and suggest that the essential nature of J is related to its role in repressing genes by promoting termination. The role of base J and H3.V in promoting RNA Polymerase II transcription termination was assessed by small RNA-seq, mRNA-seq, and strand-specific RT-PCR. Wild type cells were compared to H3.V knockout cells and to WT and H3.V knockout cells treated with dimethyloxalylglycine (DMOG) to reduce base J.
2016-07-20 | E-GEOD-77632 | biostudies-arrayexpress
Project description:ΔNp63, a master regulator of epithelial biology, is involved in regulating epithelial stem cell function, maintaining the integrity of stratified epithelial cells and committing epidermal cells to the differentiation program. To this end, ΔNp63 exploits several direct mechanisms. Here, we elucidated a novel mechanism whereby ΔNp63 efficiently sustains the expression of epidermal differentiation genes. We show that ΔNp63 interacts with Senataxin (SETX), an RNA/DNA helicase able to resolve the R-loop intermediates over the GC-rich termination sites of coding genes. Notably, we found that SETX and ΔNp63 co-regulate a subset of genes involved in the early step of the keratinocyte differentiation program. At the molecular level, SETX physically binds the p63 DNA binding motifs present in two early epidermal differentiation genes, Keratin 1 (KRT1) and ZNF750, facilitating R-loop removal over their 3’ ends and thus promoting efficient transcriptional termination and gene expression. Remarkably, SETX loss affects the activation of the proper epidermal differentiation program in vitro and impacts epidermal layer stratification in organotypic human skin. Furthermore, we found that SETX is mutated or downmodulated in SCC and SETX gene mutation is a negative prognostic factor for cutaneous SCC patient survival. Collectively, our results unveil SETX as a novel molecular player of skin homeostasis, potentially involved in hyperproliferative skin disorders.
2022-01-10 | GSE193205 | GEO
Project description:The membrane glycoprotein M6a -together with proteolipid protein (PLP), DM20 and M6b- belongs to the tetraspan PLP family. M6a is a neuronal surface protein that promotes neuronal stem cell differentiation, migration, neurite and axonal outgrowth, filopodia/spine induction and synapse formation in primary neuronal cultures and non-neuronal cell lines. M6a has two extracellular loops (EC1 and EC2), four transmembrane domains, one intracellular loop and the N and C terminus facing the cell cytoplasm. However, the complete mechanism of action or proteins associated with it through its extracellular loops remained unknown. In previous work we provided strong evidence that M6a´s extracellular loops widely contribute to its function. To asses this question, we designed and purified a chimera protein (M6a-loops as a bait protein) which was subjected to co-immunoprecipitation (Co-Ip) with rat hippocampi homogenates followed by TMT-MS. The TMT-MS and data analysis was done by the Proteomics Core Facility from the European Molecular Biology Laboratory (EMBL, Heidelberg, Germany).
2020-06-29 | PXD017347 | Pride
Project description:Breast cancer linked with BRCA1/2 mutations commonly recur and resist current therapies, including PARP inhibitors. Given the lack of effective targeted therapies for BRCA1-mutant cancers, we sought to identify novel targets to selectively kill these cancers. Here, we report that loss of RNF8 significantly protects Brca1-mutant mice against mammary tumorigenesis. RNF8 deficiency in human BRCA1-mutant breast cancer cells was found to promote R-loop accumulation and replication fork instability, leading to increased DNA damage, senescence, and synthetic lethality. Mechanistically, RNF8 interacts with XRN2, which is crucial for transcription termination and R-loop resolution. We report that RNF8 ubiquitylates XRN2 to facilitate its recruitment to R-loop-prone genomic loci and that RNF8 deficiency in BRCA1-mutant breast cancer cells decreases XRN2 occupancy at R-loop-prone sites, thereby promoting R-loop accumulation, transcription-replication collisions, excessive genomic instability, and cancer cell death. Collectively, our work identifies a synthetic lethal interaction between RNF8 and BRCA1, which is mediated by a pathological accumulation of R-loops.
2023-09-14 | GSE202723 | GEO
Project description:Posttranscriptional and posttranslational modifications play crucial roles in plant immunity. However, how plant fine-tune these two modifications to activate antiviral immunity remains unknown. Here, we report that the m6A methyltransferase TaHAKAI is utilized by wheat yellow mosaic virus (WYMV) to increase viral genomic m6A modification and promotes viral replication. However, TaHAKAI also functions as an E3 ligase that targets the viral RNA silencing suppressor P2 for degradation and inhibits viral infection. A major allele of TaHAKAI in susceptible cultivar reduced the E3 ligase activity but not m6A methyltransferase activity, promoting viral infection. Interestingly, TaHAKAIR attenuates the mRNA stability of TaWPS1, the negative regulator of spike development, to increase panicle length and spikelet number by modulating its m6A modification. Our study reveals a new mechanisms of balancing disease resistance and yield by fine-tuning m6A modification and ubiquitination.
2024-10-09 | PXD056650 | Pride
Project description:Naïve and primed pluripotent states retain distinct molecular properties, yet limited knowledge exists on how their state transitions are regulated. Here we identify Mettl3, an N6-Methyladenosine (m6A) transferase, as a regulator for terminating murine naïve pluripotency. Mettl3 knockout pre-implantation epiblasts and naïve embryonic stem cells (ESCs) are depleted for m6A in mRNAs and yet, are viable. However, they fail to adequately terminate their naïve state, and subsequently undergo aberrant and restricted lineage priming at the post-implantation stage, leading to early embryonic lethality. m6A predominantly and directly reduces mRNA stability, including that of key naïve pluripotency promoting transcripts. This study highlights a critical role for an mRNA epigenetic modification in vivo, and identifies regulatory modules that functionally influence naïve and primed pluripotency in an opposing manner.
2014-11-02 | GSE61995 | GEO