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Updated: Jul 12, 2025
Advanced Confocal Microscopy Techniques to Study Protein-protein Interactions and Kinetics at DNA Lesions
Published on: November 12, 2017
UV-induced G4 DNA structures recruit ZRF1 which prevents UV-induced senescence
Alessio De Magis1,2, Michaela Limmer1,2, Venkat Mudiyam1
1Institute of Clinical Chemistry and Clinical Pharmacology, University Hospital Bonn, Bonn, Germany.
Abstract:
Senescence has two roles in oncology: it is known as a potent tumor-suppressive mechanism, which also supports tissue regeneration and repair, it is also known to contribute to reduced patient resilience, which might lead to cancer recurrence and resistance after therapy. Senescence can be activated in a DNA damage-dependent and -independent manner. It is not clear which type of genomic lesions induces senescence, but it is known that UV irradiation can activate cellular senescence in photoaged skin. Proteins that support the repair of DNA damage are linked to senescence but how they contribute to senescence after UV irradiation is still unknown. Here, we unraveled a mechanism showing that upon UV irradiation multiple G-quadruplex (G4) DNA structures accumulate in cell nuclei, which leads to the recruitment of ZRF1 to these G4 sites. ZRF1 binding to G4s ensures genome stability. The absence of ZRF1 triggers an accumulation of G4 structures, improper UV lesion repair, and entry into senescence. On the molecular level loss of ZRF1 as well as high G4 levels lead to the upregulation of DDB2, a protein associated with the UV-damage repair pathway, which drives cells into senescence.
Insights
UV irradiation causes G-quadruplex (G4) DNA structures to accumulate, leading to senescence when ZRF1 protein is absent. This absence impairs DNA repair and upregulates DDB2, driving cells into senescence.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Cellular senescence plays a dual role in cancer, acting as a tumor suppressor while potentially contributing to therapy resistance.
- Senescence can be triggered by DNA damage, but the specific genomic lesions and mechanisms involved, particularly after UV irradiation, remain unclear.
- Proteins involved in DNA repair are linked to senescence, yet their precise contribution to UV-induced senescence is not fully understood.
Purpose of the Study:
- To elucidate the mechanism by which UV irradiation induces cellular senescence.
- To investigate the role of G-quadruplex (G4) DNA structures and ZRF1 protein in UV-induced senescence.
- To identify molecular players linking DNA repair pathways to senescence following UV exposure.
Main Methods:
- UV irradiation of cells to induce DNA damage.
- Analysis of G-quadruplex DNA structure accumulation using specific staining or antibodies.
- Assessment of ZRF1 protein recruitment to G4 sites via immunofluorescence or co-immunoprecipitation.
- Evaluation of DNA repair efficiency and DDB2 protein levels using molecular assays.
- Induction of senescence and assessment of its markers.
Main Results:
- UV irradiation leads to the accumulation of G-quadruplex (G4) DNA structures in cell nuclei.
- The protein ZRF1 is recruited to these G4 sites, where it contributes to genome stability.
- Absence or loss of ZRF1 results in increased G4 accumulation, defective UV lesion repair, and subsequent cellular senescence.
- Loss of ZRF1 and high G4 levels promote the upregulation of DDB2, a key factor in the UV-damage repair pathway, which drives senescence.
Conclusions:
- ZRF1 plays a critical role in maintaining genome stability by binding to UV-induced G-quadruplex structures.
- The ZRF1-G4 interaction is essential for proper DNA repair and preventing premature senescence after UV exposure.
- Upregulation of DDB2, triggered by ZRF1 deficiency and G4 accumulation, is a key molecular event leading to UV-induced senescence.
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