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Persistent chromatin alterations and gene expression reprogramming follow widespread DNA damage in glioblastoma

Aram S Modrek1,2,3, Ken Chandradoss4,5,6, Catherine Do7,8

  • 1Department of Radiation Oncology, Keck School of Medicine of USC, Los Angeles, CA, 90033.

Biorxiv : the Preprint Server for Biology
|July 16, 2025
PubMed

Insights

Extensive DNA damage causes lasting genetic and non-genetic changes in cells, altering gene expression and genome structure long after repair. These modifications impact cell function, potentially influencing tumor progression and resistance to therapies.

Area of Science:

  • Molecular Biology
  • Genomics
  • Cancer Research

Background:

  • DNA damage can alter gene regulation beyond mutations.
  • Long-term effects on chromatin, gene expression, and DNA modifications are not well understood.
  • Current DNA repair paradigms focus on sequence restoration.

Purpose of the Study:

  • To investigate long-term genetic and non-genetic alterations following simultaneous DNA double-strand breaks (DSBs).
  • To analyze changes in chromatin configuration, gene expression, and structural variations post-DSBs.

Main Methods:

  • Induction of numerous Cas9-mediated DSBs in human glioblastoma cells.
  • Tracking of genetic and non-genetic alterations over two weeks.
  • Analysis of genomic alterations, intra-TAD interactions, gene expression, and structural variations.

Main Results:

  • Detection of megabase-scale genomic alterations persisting for two weeks.
  • Observed shift from transient to persistent long-range cis and trans contacts.
  • Identified alterations in gene expression and associated large structural variations.

Conclusions:

  • Widespread DNA damage induces enduring genetic and non-genetic modifications.
  • These modifications alter cellular function and may impact tumor outcomes.
  • Findings suggest a role in tumor progression and the emergence of resistant cells.

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