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Publications

Journal Article Ppublish 5 citations

PubMed: 40516529 DOI: 10.1016/j.molcel.2025.04.006

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

Mol Cell 85(13):2487-2502.e12

Authors: Andreas Ingham, Ignacio Alonso de Vega, Louise Morlot, William Gittens, Ivo A Hendriks, Ellen S Kakulidis, Raimundo Freire, Norman E Davey, Julien P Duxin, Michael Lund Nielsen, Niels Mailand

Affiliations

  • Protein 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.
  • Protein Signaling Program, Novo Nordisk Foundation Center for Protein Research, University of Copenhagen, 2200 Copenhagen, Denmark.
  • Genome Damage and Stability Centre, University of Sussex, Brighton BN1 9RQ, UK.
  • Proteomics Program, Novo Nordisk Foundation Center for Protein Research, University of Copenhagen, 2200 Copenhagen, Denmark.
  • Protein Signaling Program, Novo Nordisk Foundation Center for Protein Research, University of Copenhagen, 2200 Copenhagen, Denmark; Biotech Research and Innovation Centre, University of Copenhagen, 2200 Copenhagen, Denmark.
  • Unidad de Investigación, Hospital Universitario de Canarias, Instituto de Investigación Sanitaria de Canarias (IISC), La Laguna, 38320 Santa Cruz de Tenerife, Spain; Instituto de Tecnologías Biomédicas, Centro de Investigaciones Biomédicas de Canarias, Facultad de Medicina, Campus Ciencias de la Salud, Universidad de La Laguna, 38200 Santa Cruz de Tenerife, Spain; Universidad Fernando Pessoa Canarias, 35450 Santa Maria de Guia, Spain.
  • Division of Cancer Biology, The Institute of Cancer Research, London SW3 6JB, UK.
  • Protein 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.

MeSH

Cells, Genes, Chromatin, Organelle Biogenesis, Histones, Topoisomerase Ii Inhibitors, Dna Topoisomerases, Type Ii