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Updated: Jun 4, 2025

Quantitation and Analysis of the Formation of HO-Endonuclease Stimulated Chromosomal Translocations by Single-Strand Annealing in Saccharomyces cerevisiae
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H3.1K27M-induced misregulation of the TSK/TONSL-H3.1 pathway causes genomic instability

Wenxin Yuan1, Yi-Chun Huang1, Chantal LeBlanc1

  • 1Yale University, Department of Molecular, Cellular and Developmental Biology, Faculty of Arts and Sciences; 260 Whitney Avenue, New Haven, Connecticut 06511, USA.

Biorxiv : the Preprint Server for Biology
|December 23, 2024
PubMed

Insights

The H3K27M oncohistone disrupts chromatin maturation, causing DNA damage and genomic instability. This study reveals how H3K27M impacts genome integrity, potentially contributing to diffuse midline glioma.

Area of Science:

  • Epigenetics and molecular biology
  • Plant biology and genetics
  • Cancer research

Background:

  • The H3K27M oncomutation is linked to diffuse midline glioma (DMG-H3K27a) and impairs histone mark H3K27me3 deposition, affecting cell identity.
  • While H3K27M expression causes genome integrity defects, the underlying mechanisms remain unclear.

Purpose of the Study:

  • To investigate the molecular mechanisms linking H3K27M expression to DNA damage and genomic instability.
  • To explore the role of chromatin maturation and specific proteins in H3K27M-induced genotoxicity.

Main Methods:

  • Utilized the model plant *Arabidopsis thaliana* to study H3.1K27M expression.
  • Investigated the interaction between H3.1K27M, H3.1K27 methyltransferases (ATXR5/ATXR6), and TONSOKU (TSK).
  • Assessed DNA damage, genomic alterations, and plant survival under different genetic conditions.

Main Results:

  • H3.1K27M expression disrupted post-replicative chromatin maturation by ATXR5 and ATXR6, leading to unmethylated H3.1K27 (H3.1K27me0).
  • H3.1K27me0 caused ectopic TONSOKU (TSK) activity, inducing DNA damage and genomic instability.
  • Eliminating TSK activity rescued genome stability defects, while impaired DNA repair prevented survival in H3.1K27M-expressing plants.

Conclusions:

  • H3.1K27M disrupts chromatin-based regulation of TSK/TONSL activity, leading to genomic instability.
  • These findings provide insights into the etiology of DMG-H3K27a and highlight the role of chromatin integrity in cancer development.

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