Essential roles of Jab1 in cell survival, spontaneous DNA damage and DNA repair. Oncogene 2010 Nov 18;29(46):6125-37
Date
08/31/2010Pubmed ID
20802511Pubmed Central ID
PMC3495558DOI
10.1038/onc.2010.345Scopus ID
2-s2.0-78650193203 (requires institutional sign-in at Scopus site) 53 CitationsAbstract
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.
Author List
Tian L, Peng G, Parant JM, Leventaki V, Drakos E, Zhang Q, Parker-Thornburg J, Shackleford TJ, Dai H, Lin SY, Lozano G, Rassidakis GZ, Claret FXMESH terms used to index this publication - Major topics in bold
AnimalsApoptosis
Blastocyst
COP9 Signalosome Complex
Cell Proliferation
Cell Survival
DNA Damage
DNA Repair
Embryonic Development
Intracellular Signaling Peptides and Proteins
Mice
Peptide Hydrolases
Rad51 Recombinase
Tumor Suppressor Protein p53
