Pamidi Ashwin, Cardoso Renato, Hakem Anne, Matysiak-Zablocki Elzbieta, Poonepalli Anuradha, Tamblyn Laura, Perez-Ordonez Bayardo, Hande M Prakash, Sanchez Otto, Hakem Razqallah
The Advanced Medical Discovery Institute, Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
Cancer Res. 2007 Sep 15;67(18):8527-35. doi: 10.1158/0008-5472.CAN-07-1161.
Mus81 plays an integral role in the maintenance of genome stability and DNA repair in mammalian cells. Deficiency of Mus81 in human and mouse cells results in hypersensitivity to interstrand cross-linking (ICL) agents and elevated levels of genomic instability. Furthermore, Mus81-mutant mice are susceptible to spontaneous lymphomas. The role of cellular checkpoints in mediating the phenotypes observed in Mus81-deficient cells and mice is currently unknown. In this study, we have observed increased activation of p53 in Mus81(-/-) cells in response to ICL-induced DNA damage. In addition, p53 inactivation completely rescued the ICL hypersensitivity of Mus81(-/-) cells, signifying p53 is essential for the elimination of ICL-damaged cells in the absence of Mus81. Confirming that p53 acts as a critical checkpoint for the Mus81 repair pathway, a synergistic increase of spontaneous and ICL-induced genomic instability was observed in Mus81(-/-)p53(-/-) cells. To clarify the genetic interactions of Mus81 and p53 in tumor suppression, we monitored Mus81(-/-)p53(-/-) and control mice for the development of spontaneous tumors. Significantly, we show that loss of even a single allele of Mus81 drastically modifies the tumor spectrum of p53-mutant mice and increases their predisposition to developing sarcomas. Our results reveal a key role for p53 in mediating the response to spontaneous and ICL-induced DNA damage that occurs in the absence of Mus81. Furthermore, our data show that loss of Mus81, in addition to p53, is a key step in sarcoma development.
Mus81在维持哺乳动物细胞基因组稳定性和DNA修复过程中发挥着不可或缺的作用。人和小鼠细胞中Mus81的缺失会导致对链间交联（ICL）剂超敏以及基因组不稳定性水平升高。此外，Mus81突变小鼠易患自发性淋巴瘤。目前尚不清楚细胞检查点在介导Mus81缺陷细胞和小鼠中观察到的表型方面所起的作用。在本研究中，我们观察到Mus81(-/-)细胞中p53的激活增加，以响应ICL诱导的DNA损伤。此外，p53失活完全挽救了Mus81(-/-)细胞对ICL的超敏反应，这表明在缺乏Mus81的情况下，p53对于清除ICL损伤细胞至关重要。在Mus81(-/-)p53(-/-)细胞中观察到自发性和ICL诱导的基因组不稳定性协同增加，证实p53作为Mus81修复途径的关键检查点。为了阐明Mus81和p53在肿瘤抑制中的遗传相互作用，我们监测了Mus81(-/-)p53(-/-)小鼠和对照小鼠的自发性肿瘤发生情况。值得注意的是，我们发现即使Mus81的单个等位基因缺失也会显著改变p53突变小鼠的肿瘤谱，并增加它们患肉瘤的易感性。我们的结果揭示了p53在介导对Mus81缺失时发生的自发性和ICL诱导的DNA损伤反应中的关键作用。此外，我们的数据表明，除了p53之外，Mus81的缺失是肉瘤发生的关键步骤。
