Disruption of the Cockayne Syndrome B Gene Impairs Spontaneous Tumorigenesis in Cancer-Predisposed Ink4a/ARF Knockout Mice

Cells isolated from individuals with Cockayne syndrome (CS) have a defect in transcription-coupled DNA repair, which rapidly corrects certain DNA lesions located on the transcribed strand of active genes. Despite this DNA repair defect, individuals with CS group A (CSA) or group B (CSB) do not exhibit an increased spontaneous or UV-induced cancer rate. In order to investigate the effect of CSB deficiency on spontaneous carcinogenesis, we crossed CSB(−/−) mice with cancer-prone mice lacking the p16(Ink4a)/p19(ARF) tumor suppressor locus. CSB(−/−) mice are sensitive to UV-induced skin cancer but show no increased rate of spontaneous cancer. CSB(−/−) Ink4a/ARF(−/−) mice developed 60% fewer tumors than Ink4a/ARF(−/−) animals and demonstrated a longer tumor-free latency time (260 versus 150 days). Moreover, CSB(−/−) Ink4a/ARF(−/−) mouse embryo fibroblasts (MEFs) exhibited a lower colony formation rate after low-density seeding, a lower rate of H-Ras-induced transformation, slower proliferation, and a lower mRNA synthesis rate than Ink4a/ARF(−/−) MEFs. CSB(−/−) Ink4a/ARF(−/−) MEFs were also more sensitive to UV-induced p53 induction and UV-induced apoptosis than were Ink4a/ARF(−/−) MEFs. In order to investigate whether the apparent antineoplastic effect of CSB gene disruption was caused by sensitization to genotoxin-induced (p53-mediated) apoptosis or by p53-independent sequelae, we also generated p53(−/−) and CSB(−/−) p53(−/−) MEFs. The CSB(−/−) p53(−/−) MEFs demonstrated lower colony formation efficiency, a lower proliferation rate, a lower mRNA synthesis rate, and a higher rate of UV-induced cell death than p53(−/−) MEFs. Collectively, these results indicate that the antineoplastic effect of CSB gene disruption is at least partially p53 independent; it may result from impaired transcription or from apoptosis secondary to environmental or endogenous DNA damage.