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Mechanism of Topoisomerase 2 inhibitor tolerance uncovers a fundamental histone H1 biogenesis pathway

ABSTRACT: Mechanism of Topoisomerase 2 inhibitor tolerance uncovers a fundamental histone H1 biogenesis pathway

PROVIDER: PRJNA1157362 | ENA |

REPOSITORIES: ENA

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			Action	DRS
		Other
	SRR30553924_1.fastq.gz	Fastqsanger.gz
	SRR30553924_2.fastq.gz	Fastqsanger.gz
	SRR30553926_1.fastq.gz	Fastqsanger.gz
	SRR30553926_2.fastq.gz	Fastqsanger.gz

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Similar Datasets

Mechanism of Topoisomerase 2 inhibitor tolerance uncovers a fundamental histone H1 biogenesis pathway

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

CRAMP1-dependent histone H1 biogenesis is essential for topoisomerase II inhibitor tolerance

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

CRAMP1-dependent histone H1 biogenesis is essential for topoisomerase II inhibitor tolerance [CUT&RUN]

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

CRAMP1-dependent histone H1 biogenesis is essential for topoisomerase II inhibitor tolerance [ATAC-seq]

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

CRAMP1-dependent histone H1 biogenesis is essential for topoisomerase II inhibitor tolerance [RNA-seq]

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

CRAMP1-dependent histone H1 biogenesis is essential for topoisomerase II inhibitor tolerance [CUT&RUN]

Project description:CRAMP1-dependent histone H1 biogenesis is essential for topoisomerase II inhibitor tolerance [CUT&RUN]

| PRJNA1149474 | ENA

CRAMP1-dependent histone H1 biogenesis is essential for topoisomerase II inhibitor tolerance [ATAC-seq]

Project description:CRAMP1-dependent histone H1 biogenesis is essential for topoisomerase II inhibitor tolerance [ATAC-seq]

| PRJNA1149475 | ENA

CRAMP1-dependent histone H1 biogenesis is essential for topoisomerase II inhibitor tolerance [RNA-seq]

Project description:CRAMP1-dependent histone H1 biogenesis is essential for topoisomerase II inhibitor tolerance [RNA-seq]

| PRJNA1149476 | ENA

Topoisomerase 3b Facilitates piRNA Biogenesis to Promote Transposon Silencing and Germ Cell Development

Project description:Topoisomerases typically function in nucleus to relieve topological stress in DNA. Here we show that a dual-activity topoisomerase Top3b and its partner TDRD3 largely localize in cytoplasm, and interact biochemically and genetically with piRNA processing enzymes to promote piRNA biogenesis, post-transcriptional gene silencing (PTGS) of transposons, and Drosophila germ cell development. Top3b requires its topoisomerase activity to promote PTGS of a transposon reporter, and preferentially silences long and highly-expressed transposons, suggesting that RNAs with these features may produce more topological stress for topoisomerases to solve. The double mutants between Top3b and piRNA processing enzymes exhibit stronger disruption of the signatures and levels of germline piRNAs, more de-silenced transposons, and larger defects in germ cells, than either single mutant. Our data suggest that Top3b can act in an RNA-based process—piRNA biogenesis and PTGS of transposons; and this function is required for Top3b to promote normal germ cell function.

2025-04-01 | GSE230675 | GEO

Histone H1 prevents non-CG methylation-mediated small RNA biogenesis in Arabidopsis heterochromatin

Project description:Functional genomic states are maintained by reinforcing chromatin interactions that exclude the components of other states. Plant heterochromatin features methylation of histone H3 at lysine 9 (H3K9me) and extensive DNA methylation. However, DNA methylation is also catalyzed by a mostly euchromatic small RNA-directed pathway (RdDM) thought to seek H3K9me. How RdDM is excluded from H3K9me-rich heterochromatin is unclear. Here we show that without histone H1, RdDM enters heterochromatin, preferentially at nucleosome linker DNA. Surprisingly, this does not require SHH1, the RdDM component that binds H3K9me. Furthermore, H3K9me is dispensable for RdDM, as is CG DNA methylation. Instead, we find that non-CG methylation is specifically required for small RNA biogenesis, and without H1 small RNA production quantitatively expands to non-CG methylated loci. Our results demonstrate that H1 enforces the separation of euchromatic and heterochromatic DNA methylation pathways by excluding the small RNA-generating branch of RdDM from non-CG methylated heterochromatin.

2021-12-01 | GSE179796 | GEO

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