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

Authors
  • Oh, Sunwoo
  • Bournique, Elodie
  • Bowen, Danae
  • Jalili, Pégah
  • Sanchez, Ambrocio
  • Ward, Ian
  • Dananberg, Alexandra
  • Manjunath, Lavanya
  • Tran, Genevieve P
  • Semler, Bert L
  • Maciejowski, John
  • Seldin, Marcus
  • Buisson, Rémi
Publication Date
Aug 13, 2021
Source
eScholarship - University of California
Keywords
License
Unknown
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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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