2. Academic Validation
  3. A PRMT5-ZNF326 axis mediates innate immune activation upon replication stress

A PRMT5-ZNF326 axis mediates innate immune activation upon replication stress

  • Sci Adv. 2024 Jun 7;10(23):eadm9589. doi: 10.1126/sciadv.adm9589.
Phuong Mai Hoang 1,  Denis Torre 2 3 4,  Patrick Jaynes 1,  Jessica Ho 5,  Kevin Mohammed 2 3 4 6,  Erik Alvstad 7 8,  Wan Yee Lam 4 6,  Vartika Khanchandani 1,  Jie Min Lee 1,  Chin Min Clarissa Toh 1,  Rui Xue Lee 1,  Akshaya Anbuselvan 1,  Sukchan Lee 9,  Robert P Sebra 4,  Martin J Walsh 4 6,  Ivan Marazzi 7 8,  Dennis Kappei 1 10 11,  Ernesto Guccione 2 3 4 6,  Anand D Jeyasekharan 1 11 12 13
Affiliations

Affiliations

  • 1 Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.
  • 2 Center for OncoGenomics and Innovative Therapeutics (COGIT), Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
  • 3 Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
  • 4 Department of Genetic and Genomics Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
  • 5 Programme in Emerging Infectious Diseases, Duke-NUS Medical School, Singapore, Singapore.
  • 6 Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
  • 7 Department of Biological Chemistry, University of California Irvine, Irvine, CA 92697, USA.
  • 8 Center for Epigenetics and Metabolism, University of California Irvine, Irvine, CA 92697, USA.
  • 9 Department of Integrative Biotechnology, Sungkyunkwan University, Suwon 16419, South Korea.
  • 10 Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
  • 11 NUS Centre for Cancer Research, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
  • 12 Department of Haematology-Oncology, National University Hospital, Singapore, Singapore.
  • 13 Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
PMID: 38838142 DOI: 10.1126/sciadv.adm9589
Abstract

DNA replication stress (RS) is a widespread phenomenon in carcinogenesis, causing genomic instability and extensive chromatin alterations. DNA damage leads to activation of innate immune signaling, but little is known about transcriptional regulators mediating such signaling upon RS. Using a chemical screen, we identified protein arginine methyltransferase 5 (PRMT5) as a key mediator of RS-dependent induction of interferon-stimulated genes (ISGs). This response is also associated with reactivation of endogenous retroviruses (ERVs). Using quantitative mass spectrometry, we identify proteins with PRMT5-dependent symmetric dimethylarginine (SDMA) modification induced upon RS. Among these, we show that PRMT5 targets and modulates the activity of ZNF326, a zinc finger protein essential for ISG response. Our data demonstrate a role for PRMT5-mediated SDMA in the context of RS-induced transcriptional induction, affecting physiological homeostasis and Cancer therapy.

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