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UHRF1 Overexpression Generates Distinct Senescent States with Different Tp53 Dependencies
Elena Magnani1, Charlene Chen1, Filippo Macchi1
1Program in Biology, NYU Abu Dhabi, PO Box 129188, Abu Dhabi, United Arab Emirates.
Biorxiv : the Preprint Server for Biology
|December 15, 2025
Summary
Epigenetic changes from UHRF1 overexpression create diverse senescent cells. These cells can either suppress or promote cancer, depending on UHRF1 levels and Tp53 status.
Area of Science:
- Cellular senescence
- Epigenetics
- Cancer biology
Background:
- Senescence is a complex cellular state with dual roles in cancer suppression and promotion.
- The mechanisms generating diverse senescent cell populations remain unclear.
- UHRF1 (UHRF family member 1) is an epigenetic regulator implicated in various cellular processes.
Purpose of the Study:
- To investigate how epigenetic dysregulation, specifically UHRF1 overexpression, influences the generation of diverse senescent cell populations.
- To understand the divergent fates of these senescent cells in a preneoplastic context.
Main Methods:
- Utilized a preneoplastic zebrafish liver model with hepatocyte-specific UHRF1 overexpression.
- Analyzed early cellular responses including DNA damage, DNA methylation changes, and cell cycle withdrawal.
- Assessed senescence markers, immune signatures, anti-apoptotic markers, and proliferative gene expression.
- Investigated the role of Tp53 (tumor protein p53) and UHRF1 levels in dictating cell fate.
- Evaluated the efficacy of the senolytic drug Navitoclax.
Main Results:
- UHRF1 overexpression induced double-strand breaks, DNA methylation repatterning, retrotransposon activation, and Atm/Tp53-dependent senescence.
- Diverse senescent cell populations emerged: some with immune/senescence signatures and anti-apoptotic markers, others co-expressing proliferative genes.
- Tp53 loss allowed proliferation of senescent cells with low UHRF1 but not high UHRF1.
- The senolytic Navitoclax selectively targeted only a subset of the senescent cells.
Conclusions:
- Epigenetic alterations driven by UHRF1 overexpression generate heterogeneous senescent cell populations with distinct characteristics.
- These diverse senescent cells exhibit divergent fates, influencing tumor suppression or promotion.
- Cellular senescence heterogeneity is influenced by epigenetic factors and Tp53 status, impacting therapeutic strategies.
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