Impaired phosphorylation and mis-localization of Bub1 and BubR1 are responsible for the defective mitotic checkpoint function in Brca2-mutant thymic lymphomas

Abstract

Breast cancer susceptibility gene, BRCA2, is a tumor suppressor and individuals who inherit one defected copy of BRCA2 allele experience early onset breast cancer or ovarian cancer accompanied by the loss of the wild type allele. Mouse model for Brca2 mutation shows growth retardation and paradoxical occurrence of thymic lymphomas. Thymic lymphomas from Brca2-mutant mice harbor mutations in p53, Bub1, and BubR1, which function as mitotic checkpoint proteins. Therefore, interplay between Brca2 and mitotic checkpoint has been suggested in the maintenance of genetic fidelity, although it has not been assessed whether the unique mutations in Bubl and BubR1 found in Brca2-mutant mice are responsible for the abolishment of mitotic checkpoint function. This report demonstrates that Bubl and BubR1 mutant proteins from Brca2 -/- thymic lymphomas have defects in the phosphorylation and kinetochore localization after spindle damage. Thus, the mutations of Bubl and BubR1 found in Brca2-mutant mice indeed are responsible for the chromosome instability in Brca2-mutated tumors.