RanBP2/Nup358 is a component of the nucleocytoplasmic transport machinery that has been implicated in mitotic progression. To determine the physiological importance of RanBP2 and its role in mitosis we have generated a series of mice with graded reduction of RanBP2 levels. Mice with very low amounts of RanBP2 are viable and overtly normal, but develop severe aneuploidy. Their main mitotic abnormality is the formation of anaphase bridges, a defect linked to improper topoisomerase IIα-mediated decatenation of sister chromatids. We find that RanBP2 forms a complex with topoisomerase IIα in mitosis and regulates its decatenation activity and localization to chromosomes. Furthermore, we find that RanBP2 deficient mice are prone to spontaneous tumors and carcinogen-induced skin and lung tumors. Analysis of primary human lung tumors and cellines reveals that RanBP2 downregulation is a frequent event in lung tumorigenesis. Together, these data identify RanBP2 as a key regulator of topoisomerase IIα-mediated DNA decatenation and a suppressor of aneuploidy and tumorigenesis.

98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA