An SP110-SP100 axis is a critical regulator of PML body dynamics and mitotic fidelity

Stimulation of the innate immune system by foreign RNA elicits a potent interferon response and can trigger cell death. The mechanisms by which cells balance a robust response with cell-intrinsic lethality are still being uncovered. Employing genome-wide CRISPR-Cas9 genetic screens with triphosphorylated RNA stimulation, we discover that the promyelocytic leukemia (PML) nuclear body-localized speckled protein 110 (SP110) is a potent inhibitor of type 1 interferon-driven cell death. Death suppression by SP110 counteracts a toxic activity of SP100, a major constituent of PML bodies. Loss of SP110 leads to mitotic retention of SP100 and PML bodies which associate with and perturb segregating chromosomes leading to micronucleus formation, DNA damage, and genotoxic cell death. A combination of cryo-electron microscopy, AlphaFold modeling, and cellular biochemistry reveals that SP110 dissolves toxic SP100 oligomers via necessary and sufficient direct interactions between their caspase activation and recruitment domains (CARDs). These data uncover critical roles of SP100 and SP110 in governing disassembly of PML bodies during mitosis and the repercussions if this process is mis-regulated.