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Caspase-Activated DNase localizes to cancer causing translocation breakpoints during cell differentiation

Dalal Alsowaida1,2,3, Brian D Larsen1,2, Sarah Hachmer1,2,4

  • 1The Sprott Centre for Stem Cell Research, Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa Hospital, Smyth Road, Ottawa, ON., K1H 8L6.

Biorxiv : the Preprint Server for Biology
|October 10, 2024
PubMed

Insights

Caspase activated DNase (CAD) creates DNA breaks that aid cell differentiation. Surprisingly, these breaks target genes also implicated in cancer translocations, revealing a non-pathologic role in cell fate transitions.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Genetics

Background:

  • Caspase activated DNase (CAD) induces DNA breaks, influencing cell differentiation and cancer resistance.
  • CAD's targeting activity was thought to be specific to distinct cellular processes like differentiation or cancer genesis.
  • The divergence between cell differentiation and cancer genesis suggested unique CAD target profiles for each.

Purpose of the Study:

  • To investigate the targets of CAD in differentiating muscle cells.
  • To determine if CAD targets overlap between cell differentiation and cancer-associated genes.
  • To elucidate the role of CAD in physiologic cell fate transitions.

Main Methods:

  • Analysis of CAD-bound targets in differentiating muscle cells.
  • Identification of gene pairs, such as Pax7 and Foxo1a, targeted by CAD.
  • Comparison of CAD targets in muscle cells with those in differentiating T cells.

Main Results:

  • A subset of CAD targets in differentiating muscle cells are genes involved in cancer-causing translocations.
  • CAD targets the Pax7 gene in muscle cells, reducing its expression as a prerequisite for differentiation.
  • Conserved CAD targets in T cells include genes associated with leukemia/lymphoma translocations.

Conclusions:

  • CAD targeting of translocation-prone oncogenic genes is a non-pathologic biological process.
  • This targeting mechanism is conserved across different cell types during differentiation.
  • CAD-mediated DNA breaks play a role in initiating cell fate transitions, including differentiation.

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