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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
Summary
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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