ArticleMolecular cell2025
CRAMP1-dependent histone H1 biogenesis is essential for topoisomerase II inhibitor tolerance.
Article in Molecular cell, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 4 papers.
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4 citing papers in PubMed.
- ATP2B4 driven chromatin compaction exacerbates pancreatic cancer radiotherapy resistance.Cell death discovery · 2026Article
- H1.3 depletion in AML cells prompts H1.2 redistribution, chromatin remodeling and cell cycle defects.Epigenetics & chromatin · 2026Article
- Differential control of both cell cycle-regulated and quantitative histone mRNA expression bybioRxiv : the preprint server for biology · 2026Article
- Human CRAMP1 specifically promotes the expression of histone H1 genes.EMBO reports · 2026Article
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11 authors.
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Abstract
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.
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