REQUIREMENT FOR KU80 IN GROWTH AND IMMUNOGLOBULIN V(D)J RECOMBINATION

THE DNA-dependent protein kinase (DNA-PK) is a mammalian serine/threon ine kinase that is implicated in the repair of DNA double-strand break s(1-4), DNA replication(1,5), transcription(6-8), and V(D)J recombinat ion(9-12). To determine the role of the DNA-binding subunit of DNA-PK in vivo, we targeted Ku80 in mice. In mutant mice, T and B lymphocyte development is arrested at early progenitor stages and there is a prof ound deficiency in V(D)J rearrangement. Although Ku80(-/-) mice are vi able and reproduce, they are 40-60% of the size of littermate controls . Consistent with this growth defect, fibroblasts derived from Ku80(-/ -) embryos showed an early loss of proliferating cells, a prolonged do ubling time, and intact cell-cycle checkpoints that prevented cells wi th damaged DNA from entering the cell-cycle. The unexpected growth phe notype suggests a new and important link between Ku80 and growth contr ol.