2. Academic Validation
  3. Genotoxic stress and viral infection induce transient expression of APOBEC3A and pro-inflammatory genes through two distinct pathways

Genotoxic stress and viral infection induce transient expression of APOBEC3A and pro-inflammatory genes through two distinct pathways

  • Nat Commun. 2021 Aug 13;12(1):4917. doi: 10.1038/s41467-021-25203-4.
Sunwoo Oh  # 1 2,  Elodie Bournique  # 1 2,  Danae Bowen 1 2,  Pégah Jalili 1 2,  Ambrocio Sanchez 1 2,  Ian Ward 1 2,  Alexandra Dananberg 3,  Lavanya Manjunath 1 2,  Genevieve P Tran 4,  Bert L Semler 4,  John Maciejowski 3,  Marcus Seldin 1 2,  Rémi Buisson 5 6 7
Affiliations

Affiliations

  • 1 Department of Biological Chemistry, School of Medicine, University of California Irvine, Irvine, California, USA.
  • 2 Center for Epigenetics and Metabolism, Chao Family Comprehensive Cancer Center, University of California Irvine, Irvine, California, USA.
  • 3 Molecular Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
  • 4 Department of Microbiology and Molecular Genetics, UCI Center for Virus Research, School of Medicine, University of California Irvine, Irvine, California, USA.
  • 5 Department of Biological Chemistry, School of Medicine, University of California Irvine, Irvine, California, USA. rbuisson@uci.edu.
  • 6 Center for Epigenetics and Metabolism, Chao Family Comprehensive Cancer Center, University of California Irvine, Irvine, California, USA. rbuisson@uci.edu.
  • 7 Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University of California Irvine, Irvine, California, USA. rbuisson@uci.edu.
  • # Contributed equally.
PMID: 34389714 DOI: 10.1038/s41467-021-25203-4
Abstract

APOBEC3A is a cytidine deaminase driving mutagenesis in tumors. While APOBEC3A-induced mutations are common, APOBEC3A expression is rarely detected in Cancer cells. This discrepancy suggests a tightly controlled process to regulate episodic APOBEC3A expression in tumors. In this study, we find that both viral Infection and genotoxic stress transiently up-regulate APOBEC3A and pro-inflammatory genes using two distinct mechanisms. First, we demonstrate that STAT2 promotes APOBEC3A expression in response to foreign nucleic acid via a RIG-I, MAVS, IRF3, and IFN-mediated signaling pathway. Second, we show that DNA damage and DNA replication stress trigger a NF-κB (p65/IkBα)-dependent response to induce expression of APOBEC3A and other innate immune genes, independently of DNA or RNA sensing Pattern Recognition Receptors and the IFN-signaling response. These results not only reveal the mechanisms by which tumors could episodically up-regulate APOBEC3A but also highlight an alternative route to stimulate the immune response after DNA damage independently of cGAS/STING or RIG-I/MAVS.

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