2. Academic Validation
  3. CRL4 mediates autoubiquitination of DDB1 upon deneddylation inhibition

CRL4 mediates autoubiquitination of DDB1 upon deneddylation inhibition

  • Biochem Biophys Res Commun. 2025 Oct 30:786:152772. doi: 10.1016/j.bbrc.2025.152772.
Yeong-Mu Kim 1,  Jae-Hyun Jo 1,  Dong-Kyu Kim 1,  Jong-Uk Park 1,  Dong-Hyun Jung 1,  Hyo Je Cho 1,  Hyun-A Seong 1,  Jihoon Nah 1,  Jun-Young Park 1,  Jung-Hyun Choi 1,  Sangjune Kim 2,  Kee-Beom Kim 3,  Sang-Min Jang 4
Affiliations

Affiliations

  • 1 Department of Biochemistry, Chungbuk National University, Cheongju, 28644, South Korea; Department of Biological Sciences and Biotechnology, Chungbuk National University, Cheongju, 28644, South Korea.
  • 2 Department of Biological Sciences and Biotechnology, Chungbuk National University, Cheongju, 28644, South Korea; Department of Biology, Chungbuk National University, Cheongju, 28644, South Korea.
  • 3 School of Life Science and Biotechnology, College of Natural Sciences, Kyungpook National University, Daegu, 41566, South Korea.
  • 4 Department of Biochemistry, Chungbuk National University, Cheongju, 28644, South Korea; Department of Biological Sciences and Biotechnology, Chungbuk National University, Cheongju, 28644, South Korea. Electronic address: smjang@cbnu.ac.kr.
PMID: 41066978 DOI: 10.1016/j.bbrc.2025.152772
Abstract

Cullin-RING E3 ubiquitin ligases (CRLs), activated by neddylation, mediate the ubiquitination of ∼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 β-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.

Keywords

CRL4 autoubiquitination; CSN5 inhibitor; DDB1; RepID; p97/VCP inhibitor.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-112134
    99.95%, CSN5抑制剂
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