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Essential roles of Jab1 in cell survival, spontaneous DNA damage and DNA repair

Abstract

Jun activation domain-binding protein 1 (JAB1) is a multifunctional protein that participates in the control of cell proliferation and the stability of multiple proteins. JAB1 overexpression has been implicated in the pathogenesis of human cancer. JAB1 regulates several key proteins and thereby produces varied effects on cell cycle progression, genome stability and cell survival. However, the biological significance of JAB1 activity in these cellular signaling pathways is unclear. Therefore, we developed mice that were deficient in Jab1 and analyzed the null embryos and heterozygous cells. This disruption of Jab1 in mice resulted in early embryonic lethality due to accelerated apoptosis. Loss of Jab1 expression sensitized both mouse primary embryonic fibroblasts and osteosarcoma cells to γ-radiation-induced apoptosis, with an increase in spontaneous DNA damage and homologous recombination (HR) defects, both of which correlated with reduced levels of the DNA repair protein Rad51 and elevated levels of p53. Furthermore, the accumulated p53 directly binds to Rad51 promoter, inhibits its activity and represents a major mechanism underlying the HR repair defect in Jab1-deficient cells. These results indicate that Jab1 is essential for efficient DNA repair and mechanistically link Jab1 to the maintenance of genome integrity and to cell survival.

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Acknowledgements

We thank Jeffrey Medeiros's laboratory for providing technical help, Dina Lev and Zhi-Xiang Xu for kindly providing the pRad51-luciferase reporter, Rad51 and p53 constructs and Dr Bert Vogelstein for sharing PG13-luc and MG15-Luc plasmids. We also thank Christine Wogan for assistance with the manuscript preparation. This research was supported by the National Institutes of Health Grant RO1 CA90853, the Susan G Komen for the Cure and the NIH Core Grant CA16672.

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Correspondence to F X Claret.

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Tian, L., Peng, G., Parant, J. et al. Essential roles of Jab1 in cell survival, spontaneous DNA damage and DNA repair. Oncogene 29, 6125–6137 (2010). https://doi.org/10.1038/onc.2010.345

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