A p97-PML NBs axis is essential for chromatin-bound cGAS untethering and degradation upon senescence-prone DNA damage

Abstract Cyclic GMP-AMP synthase (cGAS), initially identified as a cytosolic sensor for double-stranded DNA, is now widely recognized as a nuclear protein with distinct STING-independent functions. Its presence in the same compartment as genomic DNA highlights the critical need to regulate its nuclear levels to balance the risk of cell-intrinsic immune activation with the recognition of pathogenic DNA. The recent discovery of a proteasome-dependent degradation mechanism for chromatin-bound cGAS offers new insights into the regulation of nuclear cGAS. In this study, we examine the dynamics and stability of nuclear cGAS following DNA damage. We demonstrate that cGAS is released from chromatin in a process dependent on the p97 segregase, followed by its degradation. When protein degradation is blocked, cGAS accumulates in foci juxtaposed to PML nuclear bodies (PML NBs). We show that this juxtaposition is SUMO-dependent, with both SUMO and PML required for cGAS degradation, a process that also involves the Cullin3-RING E3 ubiquitin Ligase complex. Increasing cGAS levels on chromatin after damage by preventing its degradation expands its localization on chromatin, correlating with a dampened DNA damage response and impaired senescence entry. Overall, our findings show that a p97-PML NBs axis modulates cGAS abundance, ensuring proper regulation of the DNA damage response and balancing the possible cell-intrinsic activation of innate immune responses with senescence entry.