DNA Damage Promotes HLA Class I Presentation by Stimulating NMD-Associated Antigen Production

Antigen presentation by human leukocyte antigen (HLA) on cell surfaces is critical for the transduction of the immune signal toward cytotoxic T lymphocytes. DNA damage upregulates HLA Class I presentation; however, the mechanism is unclear. Here, we show that DNA damage upregulates HLA presentation on the surface of normal and cancer cells. DNA damage-induced HLA (di-HLA) presentation requires PSMB8/9 and TAP1/2, demonstrating that antigen production is essential. Notably, depletion of nonsense-mediated mRNA decay (NMD) components abolished di-HLA presentation. DNA damage reduced the expression of NMD transcripts in proliferative cells in an ATR-dependent manner, consistent with the requirement for ATR activity in di-HLA presentation, suggesting that DNA damage signaling stimulates the NMD process. Finally, in silico analysis identified that NMD-derived 9-mers bind to HLA and are immunogenic. Thus, our data suggest that DNA damage signaling produces immunogenic antigens by utilizing the machinery of RNA biogenesis without generating genomic mutations.