Requirement for Ku80 in growth and immunoglobulin V(D)J recombination

• Published in: Nature (London) 1996-08, Vol.382 (6591), p.551-555
• Main Authors: Nussenzweig, André, Chen, Changhu, da Costa Soares, Vera, Sanchez, Mercedes, Sokol, Karen, Nussenzweig, Michel C, Li, Gloria C
• Format: Article
• Language: English
• Subjects: Animals; Antigens, Nuclear; Base Sequence; Biological and medical sciences; Cell Cycle - physiology; Cell Division - physiology; Cell Line; Deoxyribonucleic acid; DNA; DNA Helicases; DNA Primers; DNA-Activated Protein Kinase; DNA-Binding Proteins - genetics; DNA-Binding Proteins - physiology; Fibroblasts - cytology; Fundamental and applied biological sciences. Psychology; Gene Rearrangement; Gene Rearrangement, B-Lymphocyte; Gene Rearrangement, T-Lymphocyte; Gene Targeting; Genic rearrangement. Recombination. Transposable element; Growth - physiology; Humanities and Social Sciences; Ku Autoantigen; letter; Lymphocytes; Lymphocytes - cytology; Mice; Mice, SCID; Molecular and cellular biology; Molecular biology; Molecular genetics; Molecular Sequence Data; multidisciplinary; Nuclear Proteins - genetics; Nuclear Proteins - physiology; Phosphorylation; Physical growth; Protein-Serine-Threonine Kinases - metabolism; Proteins; Rodents; Science; Science (multidisciplinary)
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/382551a0

THE DNA-dependent protein kinase (DNA-PK) is a mammalian serine/threonine kinase that is implicated in the repair of DNA double-strand breaks 1–4 , DNA replication 1,5 , transcription 6–8 , and V(D)J recombination 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 profound deficiency in V(D)J rearrangement. Although Ku80 –/– mice are viable 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 doubling time, and intact cell-cycle checkpoints that prevented cells with damaged DNA from entering the cell-cycle. The unexpected growth phenotype suggests a new and important link between Ku80 and growth control.