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S-nitrosylation of EZH2 alters PRC2 assembly, methyltransferase activity, and EZH2 stability to maintain endothelial homeostasis

Author

Listed:
  • Ashima Sakhuja

    (Pilani Campus)

  • Ritobrata Bhattacharyya

    (Pilani Campus)

  • Yash Tushar Katakia

    (Pilani Campus)

  • Shyam Kumar Ramakrishnan

    (Pilani Campus)

  • Srinjoy Chakraborty

    (Pilani Campus)

  • Hariharan Jayakumar

    (Pilani Campus)

  • Shailesh Mani Tripathi

    (Pilani Campus)

  • Niyati Pandya Thakkar

    (Pilani Campus)

  • Sumukh Thakar

    (Pilani Campus)

  • Sandeep Sundriyal

    (Pilani Campus)

  • Shibasish Chowdhury

    (Pilani Campus)

  • Syamantak Majumder

    (Pilani Campus)

Abstract

Nitric oxide (NO), a versatile bio-active molecule modulates cellular functions through diverse mechanisms including S-nitrosylation of proteins. Herein, we report S-nitrosylation of selected cysteine residues of EZH2 in endothelial cells, which interplays with its stability and functions. We detect a significant reduction in H3K27me3 upon S-nitrosylation of EZH2 as contributed by the early dissociation of SUZ12 from the PRC2. Moreover, S-nitrosylation of EZH2 causes its cytosolic translocation, ubiquitination, and degradation. Further analysis reveal S-nitrosylation of cysteine 329 induces EZH2 instability, whereas S-nitrosylation of cysteine 700 abrogates its catalytic activity. We further show that S-nitrosylation-dependent regulation of EZH2 maintains endothelial homeostasis in both physiological and pathological settings. Molecular dynamics simulation reveals the inability of SUZ12 to efficiently bind to the SAL domain of EZH2 upon S-nitrosylation. Taken together, our study reports S-nitrosylation-dependent regulation of EZH2 and its associated PRC2 complex, thereby influencing the epigenetics of endothelial homeostasis.

Suggested Citation

  • Ashima Sakhuja & Ritobrata Bhattacharyya & Yash Tushar Katakia & Shyam Kumar Ramakrishnan & Srinjoy Chakraborty & Hariharan Jayakumar & Shailesh Mani Tripathi & Niyati Pandya Thakkar & Sumukh Thakar &, 2025. "S-nitrosylation of EZH2 alters PRC2 assembly, methyltransferase activity, and EZH2 stability to maintain endothelial homeostasis," Nature Communications, Nature, vol. 16(1), pages 1-23, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-59003-x
    DOI: 10.1038/s41467-025-59003-x
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