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
  • 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. [email protected].
  • 6. Center for Epigenetics and Metabolism, Chao Family Comprehensive Cancer Center, University of California Irvine, Irvine, California, USA. [email protected].
  • 7. Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University of California Irvine, Irvine, California, USA. [email protected].
  • # 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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