CRL4 mediates autoubiquitination of DDB1 upon deneddylation inhibition

초록

Cullin-RING E3 ubiquitin ligases (CRLs), activated by neddylation, mediate the ubiquitination of similar to 20 % of cellular proteins and are central to protein homeostasis. Within the CRL4 complex, the adaptor protein DDB1 (damage-specific DNA binding protein 1) links CUL4A/B to substrate receptors (DCAFs) and is essential for various cellular processes including DNA replication, cell proliferation or DNA damage repair. Here we show that inhibition of deneddylation destabilizes DDB1 by inducing CRL4-dependent autoubiquitination of its beta-propeller A domain. Loss of DDB1, driven by CSN5i-dependent hyperactivation of CRL4 and consequent autoubiquitination, compromises CRL4 recruitment to chromatin, thereby impairing DNA replication and producing a cellular phenotype that closely resembles RepID deficiency despite intact RepID expression. Strikingly, deneddylation inhibition-induced depletion of DDB1 enhances cellular vulnerability to pharmacological inhibition of p97/valosin-containing protein (VCP) segregase, revealing an unanticipated synthetic interaction between CRL4 homeostasis and p97/VCP activity.

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