UV-induced G4 DNA structures recruit ZRF1 which prevents UV-induced senescence

Alessio Magis, Michaela Limmer, Venkat Mudiyam, David Monchaud, Stefan Juranek and Katrin Paeschke ()
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Alessio Magis: University Hospital Bonn
Michaela Limmer: University Hospital Bonn
Venkat Mudiyam: University Hospital Bonn
David Monchaud: Institut de Chimie Moléculaire de l’Université de Bourgogne (ICMUB), CNRS UMR 6302, Université de Bourgogne
Stefan Juranek: University Hospital Bonn
Katrin Paeschke: University Hospital Bonn

Nature Communications, 2023, vol. 14, issue 1, 1-16

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-42494-x

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