title: CRL4-DDB1-VPRBP ubiquitin ligase mediates the stress triggered proteolysis of Mcm10.
abstract: When mammalian cells experience radiation insult, DNA replication is stalled to prevent erroneous DNA synthesis. UV-irradiation triggers proteolysis of Mcm10, an essential human replication factor, inhibiting the ongoing replication. Here, we report that Mcm10 associates with E3 ubiquitin ligase comprising DNA damage-binding protein, DDB1, cullin, Cul4 and ring finger protein, Roc1. Depletion of DDB1, Roc1 or Cul4 abrogates the UV-triggered Mcm10 proteolysis, implying that Cul4-Roc1-DDB1 ubiquitin ligase mediates Mcm10 downregulation. The purified Cul4-Roc1-DDB1 complex ubiquitinates Mcm10 in vitro, proving that Mcm10 is its substrate. By screening the known DDB1 interacting proteins, we discovered that VprBP is the substrate recognition subunit that targets Mcm10 for degradation. Hence, these results establish that Cul4-DDB1-VprBP ubiquitin ligase mediates the stress-induced proteolysis of replication factor, Mcm10.
authors.affiliation: National Institute of Immunology, Aruna Asaf Ali Marg, New Delhi-110067, India.
authors.forename: Manpreet
authors.initials: M
authors.lastname: Kaur
authors.forename: Md Muntaz
authors.initials: MM
authors.lastname: Khan
authors.forename: Ananya
authors.initials: A
authors.lastname: Kar
authors.forename: Aparna
authors.initials: A
authors.lastname: Sharma
authors.forename: Sandeep
authors.initials: S
authors.lastname: Saxena
mesh_terms: D002352:Carrier Proteins / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000737:chemistry / Q000378:metabolism*; D002460:Cell Line; D044842:Cullin Proteins / Q000378:metabolism*; D004261:DNA Replication; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005786:Gene Expression Regulation; D006367:HeLa Cells; D006801:Humans; D064110:Minichromosome Maintenance Proteins; D017346:Protein Serine-Threonine Kinases; D017434:Protein Structure, Tertiary; D059748:Proteolysis; D013312:Stress, Physiological / Q000235:genetics; D014158:Transcription, Genetic; D044767:Ubiquitin-Protein Ligases; D054875:Ubiquitination; D014466:Ultraviolet Rays
chemical_list: C114234:CUL4A protein, human; C517832:CUL4B protein, human; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D044842:Cullin Proteins; C091435:DDB1 protein, human; D004268:DNA-Binding Proteins; C489613:MCM10 protein, human; C479529:RBX1 protein, human; D044767:Ubiquitin-Protein Ligases; C530533:DCAF1 protein, human; D017346:Protein Serine-Threonine Kinases; D064110:Minichromosome Maintenance Proteins