title: Jab1 mediates protein degradation of the Rad9-Rad1-Hus1 checkpoint complex.
abstract: The Rad1-Rad9-Hus1 (9-1-1) complex serves a dual role as a DNA-damage sensor in checkpoint signaling and as a mediator in the DNA repair pathway. However, the intercellular mechanisms that regulate the 9-1-1 complex are poorly understood. Jab1, the fifth component of the COP9 signalosome complex, has a central role in the degradation of multiple proteins and is emerging as an important regulator in cancer development. Here, we tested the hypothesis that Jab1 controls the protein stability of the 9-1-1 complex via the proteosome pathway. We provide evidence that Jab1 physically associates with the 9-1-1 complex, and show that this association is mediated through direct interaction between Jab1 and Rad1, one of the subunits of the 9-1-1 complex. Importantly, Jab1 causes translocation of the 9-1-1 complex from the nucleus to the cytoplasm, mediating rapid degradation of the 9-1-1 complex via the 26 S proteasome. Furthermore, Jab1 significantly suppresses checkpoint signaling activation, DNA synthesis recovery from blockage and cell viability after replication stresses such as UV exposure, gamma radiation and treatment with hydroxyurea. These results suggest that Jab1 is an important regulator for the stability of protein 9-1-1 control in cells, which may provide novel information on the involvement of Jab1 in the checkpoint and DNA repair signaling in response to DNA damage.
authors.affiliation: The Department of Pathology, School of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors.forename: Jin
authors.initials: J
authors.lastname: Huang
authors.forename: Honglin
authors.initials: H
authors.lastname: Yuan
authors.forename: Chongyuan
authors.initials: C
authors.lastname: Lu
authors.forename: Ximeng
authors.initials: X
authors.lastname: Liu
authors.forename: Xu
authors.initials: X
authors.lastname: Cao
authors.forename: Mei
authors.initials: M
authors.lastname: Wan
mesh_terms: D021581:Active Transport, Cell Nucleus; D000075686:COP9 Signalosome Complex; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D004247:DNA / Q000096:biosynthesis; D005092:Exonucleases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D046912:Multiprotein Complexes / Q000737:chemistry / Q000378:metabolism; D010447:Peptide Hydrolases / Q000235:genetics / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011485:Protein Binding; D015398:Signal Transduction; D020798:Two-Hybrid System Techniques
chemical_list: D018797:Cell Cycle Proteins; D047908:Intracellular Signaling Peptides and Proteins; D046912:Multiprotein Complexes; C069930:rad9 protein; D004247:DNA; D005092:Exonucleases; C113574:Rad1 protein, human; D010447:Peptide Hydrolases; C501488:COPS5 protein, human; D000075686:COP9 Signalosome Complex; D046988:Proteasome Endopeptidase Complex