Cytosolic DNA as an inhibitor of rDNA transcription

Cytosolic DNA is well established as an inducer of innate immunity through activating DNA-sensing machinery, such as the CGAS-STING1 pathway. Recently, we uncovered a previously unknown function of cytosolic DNA by elucidating its role in regulation of rDNA transcription. Cytosolic DNA interacts with UBTF and POLR1A, two essential components of the RNA polymerase I transcription machinery, thereby retaining a portion of these two proteins in the cytoplasm and resulting in an inhibition of rDNA transcription. This leads to decreased protein synthesis and reduced cell proliferation. Furthermore, STING1-induced autophagy selectively eliminates cytosolic DNA, abolishing the cytoplasmic retention of UBTF and POLR1A and consequently restoring rDNA transcription, protein synthesis, and cell proliferation. Thus, our findings reveal a DNA-sensing pathway-independent function of cytosolic DNA, which underscores cytosolic DNA as a novel player in cell metabolism.Abbreviations: cGAMP: cyclic GMP-AMP; CGAS: cyclic GMP-AMP synthase; HSV-1: herpes simplex virus-1; POLR1A: RNA polymerase I subunit A; rDNA: ribosomal DNA; rRNA: ribosomal RNA; SQSTM1: sequestosome 1; STING1: stimulator of interferon response cGAMP interactor 1; UBTF: upstream binding transcription factor.