Open AccessMEKK1-Dependent Activation of the CRL4 Complex Is Important for DNA Damage-Induced Degradation of p21 and DDB2 and Cell Survival
Author(s) -
Susanne Bacher,
Hilda Stekman,
Carla M. Farah,
Annika Karger,
Michael Kracht,
M. Lienhard Schmitz
Publication year - 2021
Publication title -
molecular and cellular biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.14
H-Index - 327
eISSN - 1067-8824
pISSN - 0270-7306
DOI - 10.1128/mcb.00081-21
Subject(s) - biology , ubiquitin ligase , dna repair , checkpoint kinase 2 , dna damage , ubiquitin , cullin , microbiology and biotechnology , nucleotide excision repair , ubiquitin protein ligases , cancer research , g2 m dna damage checkpoint , protein kinase a , kinase , cell cycle checkpoint , cell cycle , dna , genetics , cell , protein serine threonine kinases , gene
Cullin-4 ubiquitin ligase (CRL4) complexes are differentially composed and highly dynamic protein assemblies that control many biological processes, including the global genome nucleotide excision repair (GG-NER) pathway. Here, we identified the kinase mitogen-activated protein kinase kinase kinase 1 (MEKK1) as a novel constitutive interactor of a cytosolic CRL4 complex that disassembles after DNA damage due to the caspase-mediated cleavage of MEKK1. The kinase activity of MEKK1 was important to trigger autoubiquitination of the CRL4 complex by K48- and K63-linked ubiquitin chains. MEKK1 knockdown prohibited DNA damage-induced degradation of the CRL4 component DNA-damage binding protein 2 (DDB2) and the CRL4 substrate p21 and also cell recovery and survival. A ubiquitin replacement strategy revealed a contribution of K63-branched ubiquitin chains for DNA damage-induced DDB2/p21 decay, cell cycle regulation, and cell survival. These data might also have implications for cancer, as frequently occurring mutations of MEKK1 might have an impact on genome stability and the therapeutic efficacy of CRL4-dependent immunomodulatory drugs such as thalidomide derivatives.