Nuclear Accumulation of YTHDF1 Regulates mRNA Splicing in the DNA Damage Response
Ontology highlight
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.
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Project description:Innate immune signaling within cancer cells plays an important role in shaping antitumor immunity, yet the nuclear mechanisms that restrain inappropriate immune activation remain incompletely defined. YTHDF1 is an mRNA-binding protein previously characterized as a cytoplasmic m⁶A reader. Emerging evidence indicates that YTHDF1 also functions in the nucleus, where it associates with chromatin and contributes to the regulation of R-loop homeostasis. Loss of YTHDF1 results in R-loop accumulation, genomic instability, cytosolic DNA release, and activation of the cGAS–STING–type I interferon pathway. Mechanistically, YTHDF1 interacts with the chromatin remodeler ARID1A at immune-associated genomic regions, suggesting a cooperative role in maintaining genome stability and regulating immune-related transcriptional programs. To investigate the transcriptomic and chromatin-level consequences of YTHDF1 and ARID1A perturbation, we generated RNA sequencing (RNA-seq) and R-loop CUT&Tag datasets in A549 human lung cancer cells. RNA-seq was performed in two experimental settings: (1) wild-type (WT) and YTHDF1 knockout (YTHDF1-KO) cells; and (2) WT, YTHDF1-KO, ARID1A knockdown (siARID1A), and combined YTHDF1-KO with ARID1A knockdown cells. In parallel, R-loop CUT&Tag profiling was conducted under the same respective conditions to assess genome-wide R-loop distribution. These datasets provide integrated transcriptomic and chromatin profiling resources for studying the roles of YTHDF1 and ARID1A in regulating R-loop dynamics and tumor-intrinsic innate immune signaling
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Project description:Innate immune signaling within cancer cells plays an important role in shaping antitumor immunity, yet the nuclear mechanisms that restrain inappropriate immune activation remain incompletely defined. YTHDF1 is an mRNA-binding protein previously characterized as a cytoplasmic m⁶A reader. Emerging evidence indicates that YTHDF1 also functions in the nucleus, where it associates with chromatin and contributes to the regulation of R-loop homeostasis. Loss of YTHDF1 results in R-loop accumulation, genomic instability, cytosolic DNA release, and activation of the cGAS–STING–type I interferon pathway. Mechanistically, YTHDF1 interacts with the chromatin remodeler ARID1A at immune-associated genomic regions, suggesting a cooperative role in maintaining genome stability and regulating immune-related transcriptional programs. To investigate the transcriptomic and chromatin-level consequences of YTHDF1 and ARID1A perturbation, we generated RNA sequencing (RNA-seq) and R-loop CUT&Tag datasets in A549 human lung cancer cells. RNA-seq was performed in two experimental settings: (1) wild-type (WT) and YTHDF1 knockout (YTHDF1-KO) cells; and (2) WT, YTHDF1-KO, ARID1A knockdown (siARID1A), and combined YTHDF1-KO with ARID1A knockdown cells. In parallel, R-loop CUT&Tag profiling was conducted under the same respective conditions to assess genome-wide R-loop distribution. These datasets provide integrated transcriptomic and chromatin profiling resources for studying the roles of YTHDF1 and ARID1A in regulating R-loop dynamics and tumor-intrinsic innate immune signaling
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Project description:Innate immune signaling within cancer cells plays an important role in shaping antitumor immunity, yet the nuclear mechanisms that restrain inappropriate immune activation remain incompletely defined. YTHDF1 is an mRNA-binding protein previously characterized as a cytoplasmic m⁶A reader. Emerging evidence indicates that YTHDF1 also functions in the nucleus, where it associates with chromatin and contributes to the regulation of R-loop homeostasis. Loss of YTHDF1 results in R-loop accumulation, genomic instability, cytosolic DNA release, and activation of the cGAS–STING–type I interferon pathway. Mechanistically, YTHDF1 interacts with the chromatin remodeler ARID1A at immune-associated genomic regions, suggesting a cooperative role in maintaining genome stability and regulating immune-related transcriptional programs. To investigate the transcriptomic and chromatin-level consequences of YTHDF1 and ARID1A perturbation, we generated RNA sequencing (RNA-seq) and R-loop CUT&Tag datasets in A549 human lung cancer cells. RNA-seq was performed in two experimental settings: (1) wild-type (WT) and YTHDF1 knockout (YTHDF1-KO) cells; and (2) WT, YTHDF1-KO, ARID1A knockdown (siARID1A), and combined YTHDF1-KO with ARID1A knockdown cells. In parallel, R-loop CUT&Tag profiling was conducted under the same respective conditions to assess genome-wide R-loop distribution. These datasets provide integrated transcriptomic and chromatin profiling resources for studying the roles of YTHDF1 and ARID1A in regulating R-loop dynamics and tumor-intrinsic innate immune signaling
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Project description:Innate immune signaling within cancer cells plays an important role in shaping antitumor immunity, yet the nuclear mechanisms that restrain inappropriate immune activation remain incompletely defined. YTHDF1 is an mRNA-binding protein previously characterized as a cytoplasmic m⁶A reader. Emerging evidence indicates that YTHDF1 also functions in the nucleus, where it associates with chromatin and contributes to the regulation of R-loop homeostasis. Loss of YTHDF1 results in R-loop accumulation, genomic instability, cytosolic DNA release, and activation of the cGAS–STING–type I interferon pathway. Mechanistically, YTHDF1 interacts with the chromatin remodeler ARID1A at immune-associated genomic regions, suggesting a cooperative role in maintaining genome stability and regulating immune-related transcriptional programs. To investigate the transcriptomic and chromatin-level consequences of YTHDF1 and ARID1A perturbation, we generated RNA sequencing (RNA-seq) and R-loop CUT&Tag datasets in A549 human lung cancer cells. RNA-seq was performed in two experimental settings: (1) wild-type (WT) and YTHDF1 knockout (YTHDF1-KO) cells; and (2) WT, YTHDF1-KO, ARID1A knockdown (siARID1A), and combined YTHDF1-KO with ARID1A knockdown cells. In parallel, R-loop CUT&Tag profiling was conducted under the same respective conditions to assess genome-wide R-loop distribution. These datasets provide integrated transcriptomic and chromatin profiling resources for studying the roles of YTHDF1 and ARID1A in regulating R-loop dynamics and tumor-intrinsic innate immune signaling
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