Jab1/CSN5 mediates protein degradation of the Rad9/Rad1/Hus1 complex Free

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Instability of the genome in cells is an important contributor to heritable and somatic genetic changes that drive tumorigenic processes. To ensure the stability of their genomes, cells activate checkpoint signaling pathways in response to DNA damage and replication stress. The Rad1-Rad9-Hus1 (9-1-1) complex serves a dual role as a DNA-damage sensor in checkpoint signaling and as a mediator and platform for DNA repair. However, the intercellular mechanisms that regulate 9-1-1 complex level in mammalian cells are poorly understood. Jab1/CSN5, the fifth component of the COP9 signalosome complex, plays a central role in the degradation of multiple proteins in mammalian cells and is emerging as an important regulator in cancer development. Here we tested the hypothesis that Jab1/CSN5, regulates of the degradation of the 9-1-1 complex via the 26S proteosome pathway. We demonstrated that overexpression of Jab1/CSN5 enhanced chromosomal aberration and gene mutation rate in cells. We also provide evidence that Jab1 physically associates with the 9-1-1 complex. This association is mediated through direct interaction between Jab1 and Rad1. Jab1/CSN5 causes the translocation of the 9-1-1 complex from the nucleus to the cytoplasm, mediating rapid degradation of the 9-1-1 complex via the ubiquitin-proteasome pathway. The interaction of Jab1 with 9-1-1 complex is enhanced by UV exposure and hydroxyurea treatment, and the degradation of 9-1-1 complex by Jab1/CSN5 is increased significant under these replication stresses. These results indicate that Jab1/CSN5 is an important regulator for 9-1-1 complex stability control in cells, and may provide a novel mechanism underlying Jab1/CSN5-associated tumorigenesis.