Interaction of CSN4 to DDB1 regulates its stability and function in DNA damage signaling

The COP9 signalosome (CSN) regulates Cullin–RING E3 ligases (CRLs) through deneddylation and complex stabilization. However, the specific molecular functions of individual CSN subunits remain unclear. In this study, we identified CSN4 as a critical regulator of DDB1 stability and CRL4 function during the cellular response to DNA damage. CSN4 binds directly to DDB1, and its loss leads to the destabilization of DDB1, reduced CRL4 assembly, and impaired DNA damage-induced ubiquitination. The DDB1 K1131R mutant did not exhibit downregulated DDB1 expression, owing to CSN4 depletion. CSN4-resistant property showed different results in the DNA damage response, indicating that this protein is essential for the function of DDR-associated CRL. Our results also showed that This CSN4 deficiency induces autophagy, which is utilized for the degradation of DDB1. These findings provide new insights into the coordination between the ubiquitin–proteasome system and autophagy pathways in the DNA damage response. Keywords : DDB1, CSN4, Autophagy-mediated degradation, Ubiquitin-proteasome system, COP9 signalosome, CRL4 ubiquitin ligase