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

Sunwoo Oh, Elodie Bournique, Danae Bowen, Pégah Jalili, Ambrocio Sanchez, Ian Ward, Alexandra Dananberg, Lavanya Manjunath, Genevieve P. Tran, Bert L. Semler, John Maciejowski, Marcus Seldin and Rémi Buisson ()
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Sunwoo Oh: University of California Irvine
Elodie Bournique: University of California Irvine
Danae Bowen: University of California Irvine
Pégah Jalili: University of California Irvine
Ambrocio Sanchez: University of California Irvine
Ian Ward: University of California Irvine
Alexandra Dananberg: Memorial Sloan Kettering Cancer Center
Lavanya Manjunath: University of California Irvine
Genevieve P. Tran: University of California Irvine
Bert L. Semler: University of California Irvine
John Maciejowski: Memorial Sloan Kettering Cancer Center
Marcus Seldin: University of California Irvine
Rémi Buisson: University of California Irvine

Nature Communications, 2021, vol. 12, issue 1, 1-17

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-25203-4

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