Micronuclei induced by radiation, replication stress, or chromosome segregation errors do not activate cGAS-STING

Tohru Takaki; Rhona Millar; Crispin T Hiley; Simon J Boulton

doi:10.1016/j.molcel.2024.04.017

Micronuclei induced by radiation, replication stress, or chromosome segregation errors do not activate cGAS-STING

Mol Cell. 2024 May 9:S1097-2765(24)00354-X. doi: 10.1016/j.molcel.2024.04.017. Online ahead of print.

Authors

Tohru Takaki¹, Rhona Millar², Crispin T Hiley³, Simon J Boulton⁴

Affiliations

¹ DSB Repair Metabolism Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK.
² DSB Repair Metabolism Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK; Cancer Research UK Radnet City of London Centre, UCL Cancer Institute, 72 Huntley Street, London WC1E 6DD, UK.
³ Cancer Research UK Radnet City of London Centre, UCL Cancer Institute, 72 Huntley Street, London WC1E 6DD, UK.
⁴ DSB Repair Metabolism Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK; Artios Pharma Ltd., Babraham Research Campus, Meditrina Building, Cambridge CB22 3AT, UK. Electronic address: simon.boulton@crick.ac.uk.

PMID: 38749421
DOI: 10.1016/j.molcel.2024.04.017

Abstract

The cyclic guanosine monophosphate (GMP)-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway plays a pivotal role in innate immune responses to viral infection and inhibition of autoimmunity. Recent studies have suggested that micronuclei formed by genotoxic stress can activate innate immune signaling via the cGAS-STING pathway. Here, we investigated cGAS localization, activation, and downstream signaling from micronuclei induced by ionizing radiation, replication stress, and chromosome segregation errors. Although cGAS localized to ruptured micronuclei via binding to self-DNA, we failed to observe cGAS activation; cGAMP production; downstream phosphorylation of STING, TBK1, or IRF3; nuclear accumulation of IRF3; or expression of interferon-stimulated genes. Failure to activate the cGAS-STING pathway was observed across primary and immortalized cell lines, which retained the ability to activate the cGAS-STING pathway in response to dsDNA or modified vaccinia virus infection. We provide evidence that micronuclei formed by genotoxic insults contain histone-bound self-DNA, which we show is inhibitory to cGAS activation in cells.

Keywords: DNA damage; IRF3; STING; cGAS; chromosome missegregation; innate immune response; micronuclei; radiation; replication stress.