Nuclear Accumulation of YTHDF1 Regulates mRNA Splicing in the DNA Damage Response
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ABSTRACT:
PROVIDER: PRJNA1040876 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR26842351_1.fastq.gz | Fastqsanger.gz | |||
| SRR26842351_2.fastq.gz | Fastqsanger.gz | |||
| SRR26842352_1.fastq.gz | Fastqsanger.gz | |||
| SRR26842352_2.fastq.gz | Fastqsanger.gz | |||
| SRR26842353_1.fastq.gz | Fastqsanger.gz |
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Project description:YTH domain-containing family protein 1 (YTHDF1), a reader of N6-methyladenosine, has been implicated in regulating RNA metabolism in the cytosol. Here we report a role of YTHDF1 within the nucleus in response to genotoxic stress. Upon radiation, YTHDF1 is phosphorylated at serine 182 in an ATR-dependent manner. This phosphorylation inhibits exportin 1-mediated nuclear export of YTHDF1, resulting in its accumulation within the nucleus. Nuclear YTHDF1 enhances the binding capacity of SRSF2 to a group of m6A-modified exons, leading to increased exon inclusion. Specifically, YTHDF1 promotes splicing and expression of DNA repair genes, such as BRCA1 and TP53BP1, thereby mitigating excessive DNA damage. Depletion of YTHDF1 sensitizes cancer cells to radiation treatment. Altogether, our study reveals a crucial role of YTHDF1 in m6A-mediated mRNA splicing in the DNA damage response, proposing it as a potential target for radiation therapy.
2025-03-12 | GSE247891 | GEO
Project description:Nuclear metabolism and DNA damage response are intertwined processes, but the precise molecular connections remain elusive. Here, we delve into this crosstalk using as a model triple-negative breast cancer (TNBC), a subtype often prone to DNA damage accumulation. We reveal that the de novo purine synthesis enzyme Inosine monophosphate dehydrogenase 2 (IMPDH2) is enriched on chromatin in TNBC when compared to other subtypes. IMPDH2 chromatin localization is DNA damage dependent and IMPDH2 repression leads to DNA damage accumulation. On chromatin, IMPDH2 interacts and modulates Poly [ADP-ribose] polymerase 1 (PARP1) activity by controlling nuclear availability of nicotinamide adenine dinucleotide (NAD+) -a shared metabolic cofactor- to fine-tune the DNA damage response. However, when IMPDH2 is restricted to the nucleus, it depletes nuclear NAD+, leading to PARP1 cleavage and cell death. Our study identifies a non-canonical nuclear role for IMPDH2 that act as convergence point of nuclear metabolism and DNA damage response. # Contributed equally *Corresponding authors: sara.sdelci@crg.eu; marta.garciacao@crg.eu
2024-09-16 | GSE271269 | GEO
Project description:Several neurodegenerative diseases present Tau accumulation as the main pathological marker. Tau post-translational modifications such as phosphorylation and acetylation are increased in neurodegenerative patients. Here, we show that Tau hyper-acetylation at residue 174 increases its own nuclear presence and is the result of DNA damage signaling or the lack of SIRT6, both causative of neurodegeneration. Tau-K174ac is deacetylated in the nucleus by SIRT6. However, lack of SIRT6 or chronic DNA damage result in nuclear Tau-K174ac accumulation. Once there, it induces global changes in gene expression affecting protein translation, synthesis and energy production. Concomitantly, AD patients showed increased Nucleolin and a decrease in SIRT6 levels. AD patients present increased levels of nuclear Tau, particularly Tau-K174ac. Our results suggest that increased Tau-K174ac in AD patients is the result of DNA damage signaling and SIRT6 depletion. We propose that Tau-K174ac toxicity is due to its increased stability, nuclear accumulation and nucleolar dysfunction.
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Project description:The endonuclease Dicer is a key component of the human RNA interference (RNAi) pathway and known for its role in cytoplasmic micro RNA (miRNA) production. Recent findings suggest that non-canonical Dicer generates small non-coding RNA (ncRNA) to mediate the DNA damage response (DDR). Here we show that human Dicer is phosphorylated in the platform-PAZ-connector helix cassette (S1016) upon induction of DNA damage. Phosphorylated Dicer (p-Dicer) accumulates in the nucleus and is recruited to DNA double-strand breaks (DSBs). We further demonstrate that turnover of damage-induced nuclear dsRNA requires additional phosphorylation of carboxy-terminal Dicer residues (S1728 and S1852). DNA damage-induced nuclear Dicer accumulation is conserved in mammals. Dicer depletion causes spontaneous DNA damage and delays DNA repair. Taken together, we place Dicer in context of the DDR by demonstrating DNA damage-inducible phospho-switch that causes localised processing of nuclear dsRNA by p-Dicer to promote DNA repair.
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Project description:Splicing modulation is a promising treatment strategy pursued to date only in splicing-factor mutant cancers; however, its therapeutic potential is poorly understood outside of this context. Like splicing factors, genes encoding components of the cohesin complex are frequently mutated in cancer and are associated with poor outcomes in myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). Here, we show that cohesin mutations are biomarkers of sensitivity to drugs targeting splicing-factor SF3B1 (H3B-8800 and E-7107) and identify drug-induced alterations in splicing of DNA repair genes as the mechanism underlying this sensitivity. We demonstrate that treatment of cohesin-mutant cells with SF3B1 modulators results in impaired DNA damage response, accumulation of DNA damage, and increased sensitivity to a panel of chemotherapeutic agents in vitro and in vivo. Our findings expand the potential therapeutic benefits of SF3B1 splicing modulators to include cohesin-mutant MDS/AML.
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Project description:Massage therapy is commonly used for the physical rehabilitation of skeletal muscle to ameliorate pain and promote recovery from injury. While there is some evidence that massage may relieve pain in injured muscle, the cellular effects remain unknown. To assess the effects of massage, we administered either massage therapy or no treatment to separate quadriceps of eleven young, male participants after exercised-induced muscle damage. Muscle biopsies were acquired from the quadriceps (vastus lateralis) at baseline (rest), immediately after 10 minutes of massage treatment (0h), and after a 2.5 hour period of recovery. We found that massage activated the mechanotransduction signaling pathways FAK and Erk1/2, potentiated mitochondrial biogenesis signaling (nuclear PGC-1α), and mitigated the rise in NFkB (p65) nuclear accumulation caused by muscle trauma. Moreover, in spite of having no effect on muscle metabolites (glycogen, lactate), massage attenuated the production of the inflammatory cytokines TNF-α and IL-6 and reduced HSP27 phosphorylation, effectively mitigating cellular stress resulting from myofiber injury. In summary, massage therapy appears to be clinically beneficial when administered to acutely damaged skeletal muscle by reducing inflammation and promoting mitochondrial biogenesis. 55 muscle biopsies were used in this study as material to evaluate the effects of massage on gene expression. These biopsies were taken from the vastus lateralis of eleven healthy recreationally active males with full ethical approval at McMaster's university. Each individual had an initial biopsy at rest (baseline), followed by exercist testing for peak aerobic capacity. On a second visit, the individual performed a bout of exhaustive aerobic exercise, prior to recieving a randomized massage treatment to one leg. Immediatley following the exercise, subjects were allowed to recover for 10 minutes, while massage oil was lightly applied to both quadriceps. Then a single leg was randomized to recieve massage treatment for 10 minutes. Subjects then rested for 10 minutes, and one additional biopsies were carried out (on each leg). Two and half hours later (3 hours after the cessation of the exercise bout), 2 more biopsies were taken (one from each leg). This amounted to 5 biopsies from each individual.
2011-11-10 | E-GEOD-33603 | biostudies-arrayexpress
Project description:Recent studies have highlighted the critical role of metabolism in the response to DNA damage. However, the precise metabolic interactions that are set in motion to tune this fundamental process remain largely unknown. In this study, we investigated the role of nuclear metabolism in the DNA damage response using triple-negative breast cancer as a model. By comparing the chromatin-associated proteome of different breast cancer subtypes, we observed that the purine synthesis enzyme Inosine monophosphate dehydrogenase 2 (IMPDH2) is enriched in the chromatin of triple-negative breast cancer cells, which are often prone to DNA damage accumulation. Downregulation, depletion, or inhibition of IMPDH2 leads to accumulation of DNA damage. IMPDH2 chromatin localization is DNA damage dose dependent and happens at a late stage of the DNA damage repair. On chromatin, IMPDH2 interacts with PARP1. The enzymatic function of IMPDH2, which consumes NAD+, modulates PARP1 activity, thus mediating a pondered DNA damage response. However, forcing the nuclear localization of exogenous IMPDH2 provokes a dramatic NAD+ depletion that results in PARP1 cleavage and consequent cytoplasmic translocation, which mediates apoptosis. Our study identifies a moonlighting role for IMPDH2 in the control of nuclear ATP and NAD+ level, which fine-tune the activation of PARP1 and regulates the DNA damage response.
2024-11-28 | PXD043522 | Pride
Project description:Massage therapy is commonly used for the physical rehabilitation of skeletal muscle to ameliorate pain and promote recovery from injury. While there is some evidence that massage may relieve pain in injured muscle, the cellular effects remain unknown. To assess the effects of massage, we administered either massage therapy or no treatment to separate quadriceps of eleven young, male participants after exercised-induced muscle damage. Muscle biopsies were acquired from the quadriceps (vastus lateralis) at baseline (rest), immediately after 10 minutes of massage treatment (0h), and after a 2.5 hour period of recovery. We found that massage activated the mechanotransduction signaling pathways FAK and Erk1/2, potentiated mitochondrial biogenesis signaling (nuclear PGC-1α), and mitigated the rise in NFkB (p65) nuclear accumulation caused by muscle trauma. Moreover, in spite of having no effect on muscle metabolites (glycogen, lactate), massage attenuated the production of the inflammatory cytokines TNF-α and IL-6 and reduced HSP27 phosphorylation, effectively mitigating cellular stress resulting from myofiber injury. In summary, massage therapy appears to be clinically beneficial when administered to acutely damaged skeletal muscle by reducing inflammation and promoting mitochondrial biogenesis.
2011-11-10 | GSE33603 | GEO
Project description:The N6-methyladenosine (m6A) mRNA modification and the mitochondrial respiratory chain (MRC) hold paramount importance in the advancement of MASLD. This study thoroughly investigates the relationship and impact of m6A mRNA modification and mitochondrial function in the progression of MASLD. Here we report that the mRNA and protein levels of mitochondrial respiratory chain (MRC) subunits showed inconsistent trends in vivo experiments. Abnormal m6A modification and mitochondrial dysfunction in MASLD were attributed to the upregulation of methyltransferase like 3 (Mettl3) and the downregulation of YTH N6-methyladenosine RNA binding protein 1 (YTHDF1) induced by high-fat foods. Mettl3 promoted the MRC's function. However, knockout of the reader protein YTHDF1, which plays a crucial role in the m6A modification process, counteracted the effect of Mettl3 and suppressed MRC. In MASLD, damage to the MRC may be regulated by the Mettl3-m6A-YTHDF1 complex axis, especially by the role of YTHDF1. Our research has offered a novel perspective on the involvement of m6A mRNA methylation in the pathogenesis of MASLD.
2024-09-20 | PXD047819 | Pride
Project description:The nucleus is highly organized such that factors involved in transcription and processing of distinct classes of RNA are organized within specific nuclear bodies. One example is the nuclear speckle, which is defined by high concentrations of protein and non-coding RNA regulators of pre-mRNA splicing. What functional role, if any, speckles might play in the process of mRNA splicing remains unknown. Here we show that genes localized near nuclear speckles display higher spliceosome concentrations, increased spliceosome binding to their pre-mRNAs, and higher co-transcriptional splicing levels relative to genes that are located farther from nuclear speckles. We show that directed recruitment of a pre-mRNA to nuclear speckles is sufficient to increase mRNA splicing levels. Finally, we show that gene organization around nuclear speckles is highly dynamic with differential localization between cell types corresponding to differences in splicing efficiency. Together, our results integrate the longstanding observations of nuclear speckles with the biochemistry of mRNA splicing and demonstrate a critical role for dynamic 3D spatial organization of genomic DNA in driving spliceosome concentrations and controlling the efficiency of mRNA splicing.
2024-03-22 | GSE247833 | GEO