A PRMT5-ZNF326 Axis Mediates Innate Immune Activation Upon Replication Stress (Science Advances, Jun 2024)

Phuong Mai Hoang 1Denis Torre 2 3 4Patrick Jaynes 1Jessica Ho 5Kevin Mohammed 2 3 4 6Erik Alvstad 7 8Wan Yee Lam 4 6Vartika Khanchandani 1Jie Min Lee 1Chin Min Clarissa Toh 1Rui Xue Lee 1Akshaya Anbuselvan 1Sukchan Lee 9Robert P Sebra 4Martin J Walsh 4 6Ivan Marazzi 7 8Dennis Kappei 1 10 11Ernesto Guccione 2 3 4 6Anand D Jeyasekharan 1 11 12 13

Affiliations

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

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.

PMID: 38838142     DOI: 10.1126/sciadv.adm9589