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ZNF865 (BLST) Regulates Human Cell Senescence and DNA Damage

Lewis, C.; Levis, H.; Holbrook, J.; Polaski, J. T.; Jacobsen, T. D.; Gullbrand, S. E.; Diekman, B. O.; Iatridis, J. C.; Gertz, J.; Lawrence, B.; Bowles, R. D.

2025-06-18 bioengineering
10.1101/2025.06.13.659603 bioRxiv
Show abstract

Senescence has been shown to contribute to the progression of aging related diseases, yet its regulation in the intervertebral disc (IVD) remains poorly understood. Recently, ZNF865 (BLST) was identified as a previously uncharacterized zinc finger protein, that regulates a wide array of genes related to protein processing, cell senescence and DNA damage repair. Here, we show that ZNF865 expression decreases with age and pathology in human and mouse IVD samples. Depletion of ZNF865 induces senescence, SASP expression and DNA damage in both human and rat healthy NP cells. Conversely, restoration in degenerative NP cells mitigates senescence, SASP expression and DNA damage, enhances ECM anabolism, and restores chromatin accessibility and gene expression to a healthy state. In vivo, CRISPRi of ZNF865 induces disc degeneration and painful behaviors. Collectively, our findings establish ZNF865 as a regulator of genome stability and a potential therapeutic target for mediating senescence/DNA damage in aging related diseases. One Sentence SummaryZNF865 is a novel modulator of genome stability and senescence and regulates pain outcomes in the intervertebral disc via reversible senescence and DNA damage pathways.

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