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

Sunwoo Oh,Genevieve P Tran,Ambrocio Sanchez,Alexandra Dananberg,Rémi Buisson,John Maciejowski,Elodie Bournique,Pégah Jalili,Ian Ward,Marcus Seldin,Danae Bowen,Lavanya Manjunath,Bert L Semler

doi:10.1038/s41467-021-25203-4

Sunwoo Oh, Genevieve P Tran + Show 11 more

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https://doi.org/10.1038/s41467-021-25203-4

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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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APOBEC3A is a cytidine deaminase driving mutagenesis in tumors
We demonstrate that the stimulation of the transcription factor STAT2 by a retinoic acid-inducible gene I (RIG-I), mitochondrial antiviral-signaling protein (MAVS), interferon regulatory factor 3 (IRF3), and IFN-dependent immune response induces A3A expression
The first line of host defense against viruses and other infectious agents consists of the activation of innate immunity through the detection of pathogen-associated molecular patterns (PAMPs) by the host pattern recognition receptors (PRRs)

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APOBEC3A is a cytidine deaminase driving mutagenesis in tumors. While APOBEC3Ainduced mutations are common, APOBEC3A expression is rarely detected in cancer cells. 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 IFNsignaling response These results reveal the mechanisms by which tumors could episodically up-regulate APOBEC3A and highlight an alternative route to stimulate the immune response after DNA damage independently of cGAS/STING or RIG-I/MAVS. Despite the clear impact of APOBECs in viral response, mechanisms by which viral infection triggers their expression are still poorly understood In addition to their function in virus clearance, APOBEC proteins are one of the most predominant causes of genomic mutations detected in patients’ tumors[10]. A3A mRNA levels in patient tumor samples strongly correlate with A3A RNA mutations but not with A3A-induced DNA mutations[11] This discrepancy between A3A expression and mutational signatures in tumors may be caused by episodic APOBEC mutagenesis[12,36]. The specific stressors responsible for the temporary surge of A3A expression in cancer cells and mechanisms regulating A3A expression in tumors are still not known

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