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Epigenetic control of Topoisomerase 1 activity presents a cancer vulnerability

Tae-Hee Lee1, Colina X Qiao1,2, Vladislav Kuzin3

  • 1Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21287.

Biorxiv : the Preprint Server for Biology
|November 1, 2024
PubMed

Insights

The histone variant macroH2A1.1 protects the genome from DNA damage by coordinating topoisomerase 1 cleavage complex (TOP1cc) resolution. Its alternative splicing regulates this process, impacting cancer vulnerability and patient survival during TOP1 inhibitor treatment.

Area of Science:

  • Molecular Biology
  • Epigenetics
  • Genomics

Background:

  • DNA transactions create torsional stress, risking genome integrity.
  • Topoisomerase 1 (TOP1) resolves supercoiling, but aberrant TOP1:DNA cleavage complexes (TOP1ccs) cause DNA lesions.
  • Mechanisms protecting genomic hotspots from aberrant TOP1 activity are unclear.

Purpose of the Study:

  • To investigate the role of chromatin context in coordinating TOP1cc resolution.
  • To identify factors protecting against aberrant TOP1 activity at topological stress hotspots.
  • To explore the link between macroH2A1 alternative splicing, TOP1cc repair, and cancer.

Main Methods:

  • Utilized single-cell imaging to visualize transcription-induced topological stress.
  • Investigated the role of macroH2A1 isoforms (macroH2A1.1 and macroH2A1.2) in binding poly(ADP-ribose) (PAR).
  • Performed a pharmaco-genomic screen in breast cancer cells to assess sensitivity to TOP1 poisons.
  • Correlated macroH2A1 expression with patient survival data for TOP1 inhibitor-treated cancer patients.

Main Results:

  • The histone variant macroH2A1.1 binds PAR and establishes a TOP1-permissive chromatin environment.
  • The macroH2A1.2 isoform does not bind PAR and fails to protect from TOP1ccs.
  • macroH2A1.1 facilitates PAR-dependent recruitment of XRCC1 to repair TOP1ccs and prevent DNA damage.
  • Impaired macroH2A1.1 splicing, common in cancer, increased sensitivity to TOP1 poisons.
  • Low macroH2A1.1 expression correlated with improved survival in cancer patients treated with TOP1 inhibitors.

Conclusions:

  • Chromatin context, specifically the macroH2A1.1 histone variant, is crucial for coordinating TOP1cc resolution.
  • macroH2A1 alternative splicing acts as an epigenetic regulator of genome maintenance against TOP1-associated stress.
  • macroH2A1.1's role in TOP1cc repair represents a potential cancer vulnerability and therapeutic target.

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