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bioRxiv · 10.1101/2025.01.13.632830

DUSP12 promotes cell cycle progression and protects cells from cell death by regulating ZPR9

Abdusamad, M.·Guo, X.·Ramirez, I.·Velasquez, E. F.·Cohn, W.·Gholkar, A. A.·Whitelegge, J. P.·Torres, J. Z.
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Abstract

Protein phosphatases are critical for regulating cell signaling, cell cycle, and cell fate decisions, and their dysregulation leads to an array of human diseases like cancer. The dual specificity phosphatases (DUSPs) have emerged as important factors driving tumorigenesis and cancer therapy resistance. DUSP12 is a poorly characterized atypical DUSP widely conserved throughout evolution. Although no direct substrate has been firmly established, DUSP12 that has been implicated in protecting cells from stress, regulating ribosomal biogenesis, and modulating cellular DNA content. In this study, we used affinity- and proximity-based biochemical purification approaches coupled to mass spectrometry to identify the zinc finger protein ZPR9 as a novel DUSP12 interactor, which was validated by in-cell and in-vitro IP assays. Interestingly, ZPR9 binds to the unique zinc-binding domain of DUSP12, which previous reports indicated was important for many of DUSP12s functions within the cell. Prior studies had implicated ZPR9 as a modulator of apoptosis, but it remained unclear if and how ZPR9 participated in the cell cycle and, more so, how it promoted cell death. Using mass spectrometry analyses, we found that overexpression of DUSP12 promoted de-phosphorylation of ZPR9 at Ser143. Overexpression of ZPR9, but not Ser143 phosphomimetic and phosphorylation-deficient mutants, led to an increase in pre-metaphase mitotic defects while knockdown of DUSP12 also showed mitotic defects in metaphase. Furthermore, knockdown of DUSP12 promoted, while knockdown of ZPR9 suppressed, stress-induced apoptosis. Our results support a model where DUSP12 protects cells from stress-induced apoptosis by promoting de-phosphorylation of ZPR9.

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Abdusamad, M., Guo, X., Ramirez, I., Velasquez, E. F., Cohn, W., Gholkar, A. A., Whitelegge, J. P., Torres, J. Z.. 2025-01-14. DUSP12 promotes cell cycle progression and protects cells from cell death by regulating ZPR9. https://doi.org/10.1101/2025.01.13.632830

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