THE ROLE OF CYTOSOLIC DNA IN LYMPHOMA

Abstract

DNA damage response (DDR) is known to induce the expression of type I interferons (IFNs), but the underlying mechanisms are poorly understood. Here we show the presence of cytosolic DNA in different mouse and human tumor cells, and genotoxic agents increased the levels of cytosolic DNA in a DDR-dependent manner. Cloning of cytosolic DNA molecules from different mouse lymphoma cells suggests that cytosolic DNA is derived from unique genomic loci, and has the potential to form non-B DNA structures including R-loops. Overexpression of Rnaseh1, which resolves R-loops, reduced the levels of cytosolic DNA, type I Ifn transcripts and type I IFN-dependent rejection of lymphoma cells. Live cell imaging showed a dynamic contact of cytosolic DNA with mitochondria, an important organelle for nucleotide recognition by innate immune sensors. In summary, we found that DDR leads to the presence and innate immune recognition of genomic DNA in the cytosol of tumor cells.