Replication failure, genome instability, and increased cancer susceptibility in mice with a point mutation in the DNA ligase I gene.

DNA ligase I has a key role in DNA replication in the joining together of short replication intermediates. We used gene targeting to introduce a point mutation into the mouse DNA ligase I gene that was present in a human cancer patient with immunodeficiency and a cellular accumulation of DNA replication intermediates. Mutant mice grew more slowly and showed hematopoietic defects at critical stages at which the demands for DNA replication were highest. In the spleen and thymus of mutant mice, the accumulation of a sub-G1, but nonapoptotic, population was observed that we believe may represent cells with single-strand DNA breaks. In mutant bone marrow, occasional DNA replication failure was observed. The level of genome instability was significantly elevated in the spleens of DNA ligase I mutant mice and, because we have found no evidence for any DNA repair defect associated with DNA ligase I deficiency, we believe that this may result directly from the accumulation of replication intermediates. Mutant mice showed an increased incidence of spontaneous cancers with a diverse range of epithelial tumors, particularly cutaneous adnexal tumors that are rare in mice. The origin of the tumors from generalized genome instability, rather than the inactivation of one key control gene, should make DNA ligase I mutant mice a useful model to investigate the relationship between genome instability and cancer in humans.