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

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American Society for Microbiology

RESUMO

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 p16Ink4a/p19ARF 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.

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