title: VBP1 facilitates proteasome and autophagy-mediated degradation of MutS homologue hMSH4.
abstract: Ubiquitination is an important mechanism for the regulation of diverse cellular functions, including proteolysis and DNA repair. The human MutS family protein hMSH4 functions in meiotic recombinational DNA double-strand break (DSB) repair. It was previously observed that hMSH4 interacts with the von Hippel-Lindau binding protein 1 (VBP1), a partner of the VHL ubiquitin E3 ligase as well as a subunit of the prefoldin complex. In this study we address how ubiquitination regulates the homeostasis of hMSH4 in the human embryonic kidney cell line HEK293T. We demonstrate that VBP1 targets hMSH4 for degradation and identify a new VBP1 binding partner, p97, an AAA(+) ATPase involved in protein degradation and DNA damage response. VBP1, VHL, and p97 coexist in the hMSH4 immunocomplex and regulate the polyubiquitination of hMSH4. Furthermore, the results of this study demonstrate that VBP1 acts together with p97 to regulate hMSH4 degradation. Overall, this study has revealed a molecular mechanism by which VBP1 controls the levels of hMSH4 by ubiquitination in mitotic cells. Such a mechanism may be important for controlling the role of hMSH4 in regulating homologous recombination and nonhomologous DNA end joining-mediated DSB repair in human cells.
authors: 1School of Molecular Biosciences, Mail Drop 64-7520, College of Veterinary Medicine, Washington State University, Pullman, WA 99164-7520, USA. cher@wsu.edu.
authors: Yang
authors: Y
authors: Xu
authors: Chengtao
authors: C
authors: Her
mesh_terms: D000251:Adenosine Triphosphatases / Q000378:metabolism; D001343:Autophagy; D002352:Carrier Proteins / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D003598:Cytoskeletal Proteins; D057809:HEK293 Cells; D006706:Homeostasis; D006801:Humans; D018832:Molecular Chaperones; D009687:Nuclear Proteins / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D011485:Protein Binding; D059748:Proteolysis; D054875:Ubiquitination
chemical_list: D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D003598:Cytoskeletal Proteins; C409221:MSH4 protein, human; D018832:Molecular Chaperones; D009687:Nuclear Proteins; C108825:VBP1 protein, human; D046988:Proteasome Endopeptidase Complex; D000251:Adenosine Triphosphatases; C404942:p97 ATPase
keywords: DSB repair; VHL; p97; ubiquitination
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