Journal Club

Phosphorylation and chromatin tethering prevent cGAS activation during mitosis

Science 2021 Vol. 371, Issue 6535, eabc5386

Keeping cGAS silent

Cells detect microbial and self-DNA in the cytosol as a danger signal that triggers immune and inflammatory responses. Paradoxically, a large fraction of a DNA-sensing enzyme called cGAS is tightly associated with the chromatin, especially during mitosis. Li et al. uncovered two mechanisms that prevent cGAS from being activated by the chromatin DNA (see the Perspective by Ablasser). First, cGAS is hyperphosphorylated as cells enter mitosis, thereby inhibiting its DNA-binding and liquid-liquid phase separation, which promotes cGAS activation. Second, chromatin-bound cGAS is unable to oligomerize, a process required for its activation. Together, these mechanisms ensure cGAS inactivation during cell division to prevent autoimmune reactions.