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RNA exonuclease REXO4 resolves m6A-marked R-loops and suppresses anti-tumor immunity [END_seq]

ABSTRACT: To investigate the features of DNA structures that are protected by REXO4, we performed END-seq, a method that maps DSBs at nucleotide resolution in REXO4-depleted cells.

ORGANISM(S): Homo sapiens

PROVIDER: GSE313847 | GEO | 2026/05/28

REPOSITORIES: GEO

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RNA exonuclease REXO4 resolves m6A-marked R-loops and suppresses anti-tumor immunity [RNAseq]

Project description:Transcription blockage frequently occurs in tumor cells, and aberrant R-loop forming during this process drives genome instability. However, the regulation of R-loop homeostasis and its dysregulation in tumorigenesis are still under investigation. Here, we report that the RNA exonuclease REXO4 preserves genome stability by reducing excessive R-loops. Mechanistically, REXO4 resolves R-loops by 3’-5’ exonucleolytic cleavage of the RNA strand on RNA-DNA hybrids, where an accessible end is created by RNA endonuclease and N6-methyladenosine (m6A) modification on RNA moieties promotes REXO4 localization and R-loop removal. REXO4 ablation-induced DNA damage stimulates interferon response and tumor immune infiltration to suppress squamous cell carcinoma (SCC) growth and metastasis. Importantly, targeting the exonuclease activity of REXO4 via the inhibitor we developed synergizes with PD-1 blockade to inhibit SCC progression by recruiting and activating CD8+ T cells. Thus, our study provides mechanistic insight into how m6A couples with exonuclease in R-loop clearance and genome maintenance, and uncovers a druggable epi-transcriptional machinery that blocks innate immune response and enables SCC immune evasion.

2026-05-28 | GSE289625 | GEO

RNA exonuclease REXO4 resolves m6A-marked R-loops and suppresses anti-tumor immunity [RNAseq in REXO4-dTAG HeLa cells]

Project description:To determine if REXO4 depletion directly induces R-loop accumulation independent of transcription, we generated a HeLa cell line expressing endogenous REXO4 tagged with an N-terminal HA-FKBP12/F36V degron (REXO4-dTAG) via microhomology-mediated end joining (MMEJ)-based CRISPR/Cas9. Acute REXO4 degradation, achieved by a 4-hr treatment with dTAG-13 (dTAG), was then analyzed by RNA-seq to assess transcriptomic changes

2026-05-28 | GSE313849 | GEO

RNA exonuclease REXO4 resolves m6A-marked R-loops and suppresses anti-tumor immunity [CUT&Tag-seq]

Project description:To map the genome-wide distribution of R-loops and REXO4, we performed CUT&Tag-seq with antibodies against S9.6 (for R-loops) and REXO4.

2026-05-28 | GSE313850 | GEO

RNA exonuclease REXO4 resolves m6A-marked R-loops and suppresses anti-tumor immunity [ChIP-Rx]

Project description:To determine whether R-loop accumulation upon REXO4 loss results from RNA Polymerase stalling, we performed Pol II chromatin-immunoprecipitation followed by sequencing with reference exogenous genome (ChIP-Rx).

2026-05-28 | GSE313845 | GEO

RNA exonuclease REXO4 resolves m6A-marked R-loops and suppresses anti-tumor immunity

Project description:This SuperSeries is composed of the SubSeries listed below.

2026-05-28 | GSE289626 | GEO

RNA exonuclease REXO4 resolves m6A-marked R-loops and suppresses anti-tumor immunity [MRC-seq]

Project description:To achieve a more specific mapping of m6A-marked R-loops, we developed an m6A-marked R-loop CUT&Tag sequencing (MRC-seq) approach to map m6A-marked R-loops, which involves the specific isolation of R-loops using an S9.6 antibody-based CUT&Tag approach followed by m6A immunoprecipitation.

2026-05-28 | GSE313848 | GEO

DRIP-seq reveals REXO4 and RNaseH1 work together to process R-loops in the same genomic region across the genome.

Project description:Endonuclease RNaseH1 acts as a common R-loop resolvase to prevent R-loop accumulation genome-widely, whether there is any exonuclease complementing RNaseH1 to more efficiently resolve R-loops is worth investigation. Here we identify an exonuclease REXO4, which collaborates with RNaseH1 to efficiently degrade R-loops in an “endo- and exo-cleavage coupling” manner.DNA-RNA immunoprecipitation followed by sequencing (DRIP-seq) shows that R-loop regions regulated by REXO4 highly overlap with those regulated by RNaseH1.

2026-01-08 | GSE253653 | GEO

Senataxin resolves R-loops forming at DNA double strand breaks to prevent translocations

Project description:DNA Double Strands Breaks (DSBs) are highly detrimental since they can lead to mutations and chromosomes rearrangements (amplification, deletion, translocation and chromosome loss). Here, we set to assess the role of senataxin, a RNA:DNA helicase involved in the regulation of transcription and the maintenance of genome integrity, at sites of DNA Double Strand Breaks. We performed ChIP-Seq mapping of senataxin before and after damage, genome-wide DNA:RNA hybrids (DRIP) mapping before and after damage. We also performed RNA-Seq and RNA pol II mapping (total and phosphorylated on serine 2 of the CTD) by ChIP-Seq in undamaged cells to discriminate between damage in active versus inactive regions.

2018-02-20 | E-MTAB-6318 | biostudies-arrayexpress

Efficient processing of widespread R-loops through an endo- and exo-cleavage coupling mode prevents genome instability

Project description:Excessive accumulation of R-loops is thought to be one of the major causes of genome instability. Endonuclease RNaseH1 acts as a classic, common R-loop resolvase to prevent R-loop accumulation genome-widely, whether there is any exonuclease complementing and teaming up with RNaseH1 to more efficiently resolve genome-wide R-loops is worth investigation. Here we identify an exonuclease REXO4, which collaborates with RNaseH1 endonuclease to more efficiently degrade R-loops in an “endo- and exo-cleavage coupling” manner. Specifically, among many members of DEDDh exonuclease family, REXO4 has the most significant effect on R-loop suppression. REXO4 directly degrades RNA strand in R-loop from the end or internal nick through its 3’-5’ exonuclease activity, and also stimulates RNaseH1 endonuclease activity. The genome-wide R-loop regions regulated by REXO4 highly overlap with those regulated by RNaseH1, and REXO4 overexpression counteracts genome-wide R-loop accumulation caused by RNaseH1 deficiency. Furthermore, REXO4-deficient tumors display elevated R-loop mutation burden, and tumor patient-derived mutations in REXO4 enzymatic region all impair R-loop cleavage activity. Interfering with REXO4 increases the sensitivity of tumor cells to alkylating and G4 stabilizing drugs. Therefore, our study proposes a model for highly efficient processing of genome-wide R-loops by endo- and exo-cleavage, which provides additional insights into understanding the link between R-loop associated genome instability and tumors.

2026-01-08 | GSE269749 | GEO

DRIP-seq reveals REXO4 and RNaseH1 work together to process R-loops in the same genomic region across the genome.

Project description:DRIP-seq reveals REXO4 and RNaseH1 work together to process R-loops in the same genomic region across the genome.

| PRJNA1066715 | ENA