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Simple and Fast Rolling Circle Amplification-Based Detection of Topoisomerase 1 Activity in Crude Biological Samples
Published on: December 2, 2022
CRAMP1-dependent histone H1 biogenesis is essential for topoisomerase II inhibitor tolerance
Andreas Ingham1, Ignacio Alonso de Vega2, Louise Morlot2
1Protein Signaling Program, Novo Nordisk Foundation Center for Protein Research, University of Copenhagen, 2200 Copenhagen, Denmark; Center for Chromosome Stability, Department of Cellular and Molecular Medicine, University of Copenhagen, 2200 Copenhagen, Denmark.
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.
Insights
The protein CRAMP1 and histone H1 are crucial for tolerating topoisomerase II (TOP2) inhibitors (TOP2i) in human cells. CRAMP1 maintains histone H1 supply, preventing TOP2 exhaustion and DNA damage.
Area of Science:
- Molecular Biology
- Genetics
- Cancer Research
Background:
- Topoisomerase II (TOP2) inhibitors are vital chemotherapy drugs.
- These agents stabilize TOP2-DNA complexes, leading to DNA damage and impacting genome integrity.
Purpose of the Study:
- To identify key factors influencing tolerance to TOP2 inhibitors in human cells.
- To elucidate the role of the uncharacterized protein CRAMP1 and histone H1 in TOP2 inhibitor response.
Main Methods:
- Investigated the function of CRAMP1 in human cells.
- Analyzed the impact of CRAMP1 and histone H1 on TOP2 inhibitor tolerance.
- Studied the mechanism of H1 biogenesis and its relation to TOP2 activity.
Main Results:
- Identified CRAMP1 as a critical regulator of histone H1 biogenesis.
- Demonstrated that CRAMP1 maintains H1 supply, enhancing tolerance to TOP2 inhibitors.
- Revealed a novel mechanism where reduced H1 pool amplifies TOP2 demand, leading to TOP2 exhaustion.
Conclusions:
- CRAMP1 is a key effector of TOP2 inhibitor tolerance by regulating histone H1 supply.
- The findings elucidate histone H1 biogenesis and offer strategies for cancer therapy targeting H1 deficiency.
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