DNAR-11. NUCLEAR POTASSIUM GOVERNS NUCLEAR ENVELOPE INTEGRITY AND GENOMIC STRUCTURE IN MEDULLOBLASTOMA

Abstract

Abstract Potassium is the most abundant intracellular cation with crucial functions such as regulating cell proliferation, migration, and differentiation. Potassium flux across cellular membranes is controlled by potassium channels. While the role of cytosolic potassium has been researched for many decades, very little is known about the modulation or significance of potassium in the cell nucleus. Here, we identify potassium channel subunit KCNG1 as a novel regulator of nuclear potassium in medulloblastoma (MB), the most common malignant pediatric brain tumour. Using genetically encoded Förster resonance energy transfer (FRET)-based potassium sensors, we show that KCNG1 regulates nuclear potassium level independently of cytosolic potassium level. KCNG1 knockdown alters the genomic architecture of MB cells by stabilizing G-quadruplex (G4) DNA, inducing DNA damage, and reducing nuclear envelope-associated heterochromatin. Ultimately, KCNG1 deficiency results in nuclear swelling, thereby compromising nuclear envelope integrity and inducing DNA spillage into the cytosol to activate the pro-inflammatory cGAS/STING pathway. Genetic knockdown of KCNG1 mitigates tumour growth and prolongs the survival of mice bearing MB of distinct subgroups. Altogether, our findings reveal that nuclear potassium regulates genomic structure and nuclear envelope integrity and demonstrate that targeting a nuclear potassium channel can be leveraged to activate immunogenic signalling in MB.