CRAMP1-dependent histone H1 biogenesis is essential for topoisomerase II inhibitor tolerance [CUT&RUN]
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1149474 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| Other | ||||
| SRR30290849_1.fastq.gz | Fastqsanger.gz | |||
| SRR30290849_2.fastq.gz | Fastqsanger.gz | |||
| SRR30290850_1.fastq.gz | Fastqsanger.gz | |||
| SRR30290850_2.fastq.gz | Fastqsanger.gz |
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Project description:Topoisomerase II (TOP2) inhibitors (TOP2i) are mainstay chemotherapeutic agents that undermine genome integrity by stabilizing TOP2-DNA complexes accompanied by DNA damage formation. Here, we reveal the uncharacterized protein CRAMP1 and H1 linker histones as key effectors of TOP2i tolerance in human cells. We demonstrate that CRAMP1 defines a dedicated histone H1 biogenesis factor stimulating transcription of both replicative and non-replicative H1 genes, driven by its concurrent targeting to histone gene loci and H1-specific promoter motifs. CRAMP1 promotes TOP2i tolerance by maintaining H1 supply, involving a novel mechanism uncoupled from TOP2i-induced DNA damage whereby reducing the H1 pool triggers unscheduled TOP2 substrate formation in low-accessibility chromatin states. This amplifies total demand for TOP2 activity, lowering the threshold for TOP2i-mediated exhaustion of TOP2. Our discoveries elucidate the mechanistic basis of histone H1 biogenesis in human cells, opening opportunities for selectively manipulating linker but not core histone supply and targeting cancer-associated H1 deficiency.
2025-06-13 | PXD053086 | Pride
Project description:Topoisomerase II (TOP2) inhibitors (TOP2i) are mainstay chemotherapeutic agents that undermine genome integrity by stabilizing TOP2-DNA complexes accompanied by DNA damage formation. Here, we reveal the uncharacterized protein CRAMP1 and H1 linker histones as key effectors of TOP2i tolerance in human cells. We demonstrate that CRAMP1 defines a dedicated histone H1 biogenesis factor stimulating transcription of both replicative and non-replicative H1 genes, driven by its concurrent targeting to histone gene loci and H1-specific promoter motifs. CRAMP1 promotes TOP2i tolerance by maintaining H1 supply, involving a novel mechanism uncoupled from TOP2i-induced DNA damage whereby reducing the H1 pool triggers unscheduled TOP2 substrate formation in low accessibility chromatin states. This amplifies total demand for TOP2 activity, lowering the threshold for TOP2i-mediated exhaustion of TOP2. Our discoveries elucidate the mechanistic basis of histone H1 biogenesis in human cells, opening opportunities for selectively manipulating linker but not core histone supply and targeting cancer-associated H1 deficiency.
2025-06-13 | GSE275117 | GEO
Project description:Topoisomerase II (TOP2) inhibitors (TOP2i) are mainstay chemotherapeutic agents that undermine genome integrity by stabilizing TOP2-DNA complexes accompanied by DNA damage formation. Here, we reveal the uncharacterized protein CRAMP1 and H1 linker histones as key effectors of TOP2i tolerance in human cells. We demonstrate that CRAMP1 defines a dedicated histone H1 biogenesis factor stimulating transcription of both replicative and non-replicative H1 genes, driven by its concurrent targeting to histone gene loci and H1-specific promoter motifs. CRAMP1 promotes TOP2i tolerance by maintaining H1 supply, involving a novel mechanism uncoupled from TOP2i-induced DNA damage whereby reducing the H1 pool triggers unscheduled TOP2 substrate formation in low accessibility chromatin states. This amplifies total demand for TOP2 activity, lowering the threshold for TOP2i-mediated exhaustion of TOP2. Our discoveries elucidate the mechanistic basis of histone H1 biogenesis in human cells, opening opportunities for selectively manipulating linker but not core histone supply and targeting cancer-associated H1 deficiency.
2025-06-13 | GSE275116 | GEO
Project description:Topoisomerase II (TOP2) inhibitors (TOP2i) are mainstay chemotherapeutic agents that undermine genome integrity by stabilizing TOP2-DNA complexes accompanied by DNA damage formation. Here, we reveal the uncharacterized protein CRAMP1 and H1 linker histones as key effectors of TOP2i tolerance in human cells. We demonstrate that CRAMP1 defines a dedicated histone H1 biogenesis factor stimulating transcription of both replicative and non-replicative H1 genes, driven by its concurrent targeting to histone gene loci and H1-specific promoter motifs. CRAMP1 promotes TOP2i tolerance by maintaining H1 supply, involving a novel mechanism uncoupled from TOP2i-induced DNA damage whereby reducing the H1 pool triggers unscheduled TOP2 substrate formation in low accessibility chromatin states. This amplifies total demand for TOP2 activity, lowering the threshold for TOP2i-mediated exhaustion of TOP2. Our discoveries elucidate the mechanistic basis of histone H1 biogenesis in human cells, opening opportunities for selectively manipulating linker but not core histone supply and targeting cancer-associated H1 deficiency.
2025-06-13 | GSE275115 | GEO
Project description:Topoisomerase 2 (TOP2) inhibitors (TOP2i) are mainstay cancer chemotherapeutic agents that undermine genome integrity by stabilizing TOP2-DNA complexes. Nevertheless, their clinical deployment is associated with toxicity, acquired resistance and secondary malignancies, necessitating the development of improved treatment strategies. From genome-scale CRISPR-Cas9 screens, we discovered that the uncharacterized human protein CRAMP1 and H1 linker histones display synthetic lethal interactions with TOP2i. Although loss of CRAMP1 selectively hypersensitizes cells to TOP2i but not other genotoxic agents, we show that CRAMP1 does not function as a conventional repair factor for TOP2-DNA complexes. Instead, CRAMP1 defines an H1-specific histone biogenesis factor, and we demonstrate that reduced histone H1 abundance underlies TOP2i hypersensitivity in CRAMP1-deficient cells. Mechanistically, CRAMP1 acts as a transcription factor for both replicative and non-replicative H1 genes, driven by its concurrent targeting to histone gene loci and H1-specific promoter motifs. We establish that defective H1 biogenesis induces TOP2i hypersensitization via a novel paradigm uncoupled from DNA repair, increasing cellular demand for TOP2 activity through extensive formation of novel TOP2 substrates due to chromatin decompaction, thereby lowering the threshold for TOP2i-induced cytotoxicity. Collectively, through revealing CRAMP1-dependent H1 synthesis as an essential prerequisite for TOP2i resistance, our findings elucidate the mechanistic basis of linker histone biogenesis in human cells and provide a framework for delineating H1 functions in chromatin biology.
2025-06-13 | GSE276436 | GEO
Project description:CRAMP1-dependent histone H1 biogenesis is essential for topoisomerase II inhibitor tolerance [ATAC-seq]
| PRJNA1149475 | ENA
Project description:CRAMP1-dependent histone H1 biogenesis is essential for topoisomerase II inhibitor tolerance [RNA-seq]
| PRJNA1149476 | ENA
Project description:Mechanism of Topoisomerase 2 inhibitor tolerance uncovers a fundamental histone H1 biogenesis pathway
| PRJNA1157362 | ENA
Project description:The essential role of the core histones (H2A, H2B, H3 and H4) in DNA packaging has been well understood for decades, but the function of the linker histone (H1) remains enigmatic. H1 compacts nucleosome arrays in vitro, but the multiple H1 subtypes and variants encoded in mammalian genomes (11 in both mice and humans) hamper genetic studies to determine H1 function in vivo. Challenging the prevailing view that linker histones are a general feature of heterochromatin, here we show a critical requirement for linker histones in the function of Polycomb Repressive complex 2 (PRC2). Through a CRISPR/Cas9 genetic screen in a fluorescent reporter cell line responsive to PRC2 perturbation, we identified an essential requirement for the poorly characterised gene CRAMP1 in PRC2-mediated repression. CRAMP1 localises to the promoters of all expressed H1 genes where it acts as a positive transcriptional regulator. Ablation of CRAMP1 provides a unique tool to simultaneously deplete all linker histones, which results in selective decompaction of H3K27me3-marked loci and derepression of PRC2 target genes without concomitant loss of PRC2 occupancy or enzymatic activity. Strikingly, in contrast to the broad genomic distribution previously ascribed to H1, we find that linker histones selectively localise to genomic loci marked by H3K27me3 across diverse cell types and organisms. Altogether, our data demonstrate a prominent role for linker histones in epigenetic repression by PRC2.
2025-06-13 | GSE276852 | GEO
Project description:The essential role of the core histones (H2A, H2B, H3 and H4) in DNA packaging has been well understood for decades, but the function of the linker histone (H1) remains enigmatic. H1 compacts nucleosome arrays in vitro, but the multiple H1 subtypes and variants encoded in mammalian genomes (11 in both mice and humans) hamper genetic studies to determine H1 function in vivo. Challenging the prevailing view that linker histones are a general feature of heterochromatin, here we show a critical requirement for linker histones in the function of Polycomb Repressive complex 2 (PRC2). Through a CRISPR/Cas9 genetic screen in a fluorescent reporter cell line responsive to PRC2 perturbation, we identified an essential requirement for the poorly characterised gene CRAMP1 in PRC2-mediated repression. CRAMP1 localises to the promoters of all expressed H1 genes where it acts as a positive transcriptional regulator. Ablation of CRAMP1 provides a unique tool to simultaneously deplete all linker histones, which results in selective decompaction of H3K27me3-marked loci and derepression of PRC2 target genes without concomitant loss of PRC2 occupancy or enzymatic activity. Strikingly, in contrast to the broad genomic distribution previously ascribed to H1, we find that linker histones selectively localise to genomic loci marked by H3K27me3 across diverse cell types and organisms. Altogether, our data demonstrate a prominent role for linker histones in epigenetic repression by PRC2.
2025-06-13 | GSE276863 | GEO