p19Arf is required for the cellular response to chronic DNA damage

• Published in: Oncogene 2016-08, Vol.35 (33), p.4414-4421
• Main Authors: Bieging-Rolett, K T, Johnson, T M, Brady, C A, Beaudry, V G, Pathak, N, Han, S, Attardi, L D
• Format: Article
• Language: English
• Subjects: 631/208/68; 631/67/581; 631/67/68; 631/80/509; Apoptosis; Cell Biology; Cell culture; Cell cycle; Cellular biology; Deoxyribonucleic acid; DNA; DNA damage; DNA repair; Embryo fibroblasts; Genetic research; Human Genetics; Hydroxyurea; Internal Medicine; Medicine; Medicine & Public Health; Oncology; Senescence; Sensors; short-communication; Tumor proteins; Tumor suppressor genes; Tumors; γ Radiation
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2015.490

The p53 tumor suppressor is a stress sensor, driving cell cycle arrest or apoptosis in response to DNA damage or oncogenic signals. p53 activation by oncogenic signals relies on the p19 Arf tumor suppressor, while p53 activation downstream of acute DNA damage is reported to be p19 Arf -independent. Accordingly, p19 Arf -deficient mouse embryo fibroblasts (MEFs) arrest in response to acute DNA damage. However, p19 Arf is required for replicative senescence, a condition associated with an activated DNA damage response, as p19 Ar f −/− MEFs do not senesce after serial passage. A possible explanation for these seemingly disparate roles for p19 Arf is that acute and chronic DNA damage responses are mechanistically distinct. Replicative senescence may result from chronic, low-dose DNA damage responses in which p19 Arf has a specific role. We therefore examined the role of p19 Arf in cellular responses to chronic, low-dose DNA-damaging agent treatment by maintaining MEFs in low oxygen and administering 0.5 G y γ-irradiation daily or 150 μ M hydroxyurea, a replication stress inducer. In contrast to their response to acute DNA damage, p19 Ar f −/− MEFs exposed to chronic DNA damage do not senesce, revealing a selective role for p19 Arf in senescence upon low-level, chronic DNA damage. We show further that p53 pathway activation in p19 Ar f −/− MEFs exposed to chronic DNA damage is attenuated relative to wild-type MEFs, suggesting a role for p19 Arf in fine-tuning p53 activity. However, combined Nutlin3a and chronic DNA-damaging agent treatment is insufficient to promote senescence in p19 Ar f −/− MEFs, suggesting that the role of p19 Arf in the chronic DNA damage response may be partially p53-independent. These data suggest the importance of p19 Arf for the cellular response to the low-level DNA damage incurred in culture or upon oncogene expression, providing new insight into how p19 Arf serves as a tumor suppressor. Moreover, our study helps reconcile reports suggesting crucial roles for both p19 Arf and DNA damage-signaling pathways in tumor suppression.