When the innate immune system meets mitosis consequences of sensing mitotic chromosomes by cGAS
In eukaryotes, genomic chromosomal DNAs are normally encapsulated by the nuclear envelope, which limits access of cytoplasmic materials. Invasion of foreign DNAs in the cytoplasm is sensed by the cytoplasmic DNA sensor, cGAS, which stimulates inflammatory signaling pathways, through synthesizing the second messenger cyclic GMP-AMP (cGAMP). While the nuclear envelope may restrict cGAS from freely binding to chromosomal DNAs during interphase, cGAS does interact with chromosomes when the nuclear envelope breaks down in mitosis. In this seminar, I will describe our recent findings on regulation and functional significance of cGAS binding to mitotic chromosomes. We found that cGAS activation is attenuated upon binding to nucleosomes, but when cells are arrested in mitosis for a prolonged period, the cGAS pathway promotes apoptosis via a p53-independent mechanism. The potential importance of the cGAS pathway in tumors for anti-mitotic chemotherapy will be discussed.
Professor, Head of Laboratory, The Rockefeller University, New York, USA
Domain 4 - UMR 144 - Subcellular Structure and Cellular Dynamics