Fig. 6

Physiological relevance of BRE overexpression. a Immunohistological staining of 15 BRCA2-deficient tumors using BRE and CDC25A antibodies. Numbers represent different tumor numbers. Control represents staining with control IgG. H: high expression, L: low expression. b Allograft tumor growth of KB2P1.21 (Brca2 negative) cells with and without stable expression of HA-BRE. Values are represented as mean ± s.e.m. P values were calculated using ANCOVA test. c Western blot showing the expression of HA-BRE and CDC25A in tumors from allograft experiment. GAPDH was used as control. d Proposed model explaining the survival of BRE overexpressed BRCA2-deficient cells. CDC25A protein stabilization is regulated by the balanced action of ubiquitylation and deubiquitylation mediated by β-TRCP and DUB3, respectively. In cells with normal BRE expression level, loss of BRCA2 induces DNA damage that leads to β-TRCP-mediated degradation of CDC25A and cells undergo cell cycle arrest and apoptosis. BRCA2 loss in BRE overexpressing cells results an increase in BRE/USP7/CDC25A complex that perturbs the balance of CDC25A ubiquitylation/deubiquitylation and leads to an increase in CDC25A even in presence of DNA damage. This elevated level of CDC25A leads to the survival of cells with damaged DNA