Shen Yu J, Le Bert Nina, Chitre Anuja A, Koo Christine Xing'Er, Nga Xing H, Ho Samantha S W, Khatoo Muznah, Tan Nikki Y, Ishii Ken J, Gasser Stephan
Immunology Programme and Department of Microbiology, Centre for Life Sciences, National University of Singapore, Singapore 117456, Singapore; NUS Graduate School for Integrative Sciences & Engineering, National University of Singapore, Singapore 117456, Singapore.
Immunology Programme and Department of Microbiology, Centre for Life Sciences, National University of Singapore, Singapore 117456, Singapore.
Cell Rep. 2015 Apr 21;11(3):460-73. doi: 10.1016/j.celrep.2015.03.041. Epub 2015 Apr 9.
The DNA damage response (DDR) induces 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. Treatment of cells with genotoxic agents increased the levels of cytosolic DNA in a DDR-dependent manner. Cloning of cytosolic DNA molecules from 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 innate immune recognition of cytosolic nucleotides. In summary, we found that cytosolic DNA is present in many tumor cells and contributes to the immunogenicity of tumor cells.
DNA损伤反应（DDR）可诱导I型干扰素（IFN）的表达，但其潜在机制尚不清楚。在此，我们展示了不同小鼠和人类肿瘤细胞中胞质DNA的存在。用基因毒性剂处理细胞以DDR依赖的方式增加了胞质DNA的水平。从小鼠淋巴瘤细胞中克隆胞质DNA分子表明，胞质DNA来源于独特的基因组位点，并有可能形成非B型DNA结构，包括R环。可解决R环的Rnaseh1的过表达降低了胞质DNA水平、I型Ifn转录本水平以及I型干扰素依赖的淋巴瘤细胞排斥反应。活细胞成像显示胞质DNA与线粒体存在动态接触，线粒体是对胞质核苷酸进行天然免疫识别的重要细胞器。总之，我们发现胞质DNA存在于许多肿瘤细胞中，并有助于肿瘤细胞的免疫原性。
