The Mre11͞Rad50 protein complex functions in diverse aspects of the cellular response to doublestrand breaks (DSBs), including the detection of DNA damage, the activation of cell cycle checkpoints, and DSB repair. Whereas genetic analyses in Saccharomyces cerevisiae have provided insight regarding DSB repair functions of this highly conserved complex, the implication of the human complex in Nijmegen breakage syndrome reveals its role in cell cycle checkpoint functions. We established mRad50 mutant mice to examine the role of the mammalian Mre11͞Rad50 protein complex in the DNA damage response. Early embryonic cells deficient in mRad50 are hypersensitive to ionizing radiation, consistent with a role for this complex in the repair of ionizing radiation-induced DSBs. However, the null mrad50 mutation is lethal in cultured embryonic stem cells and in early developing embryos, indicating that the mammalian Mre11͞Rad50 protein complex mediates functions in normally growing cells that are essential for viability.DNA damage is induced by extrinsic agents such as ionizing radiation and also arises spontaneously as an outcome of cellular processes such as DNA replication and oxidative metabolism. The cellular response to DNA damage involves the integration of pathways that detect and signal the presence of DNA damage, activate DNA damage-dependent cell cycle checkpoints, and mediate DNA repair. Genetic defects that impair any of these aspects of the cellular DNA damage response invariably lead to genomic instability. Studies in Saccharomyces cerevisiae and human cells have shown that the Mre11͞Rad50 protein complex functions in DNA damage detection and signaling as well as in the repair of DNA double-strand breaks (DSBs) (1-3). Hence, this highly conserved protein complex appears to play a central role in the cellular response to DSBs, linking DSB repair to cell cycle checkpoint functions.Genetic analyses indicate that in mitotic cells, the S. cerevisiae Mre11͞Rad50 protein complex functions in the repair of chromosomal DSBs through nonhomologous end joining (4-7). Mutations affecting the S. cerevisiae complex also lead to genomic instability in the form of increased chromosome loss and spontaneous loss of heterozygosity (i.e., allelic recombination) (2). In meiosis, the S. cerevisiae Mre11͞Rad50͞Xrs2 protein complex is critical to the initiation of meiotic recombination (8). In addition to these roles in DNA recombination and repair, recent data suggest that the S. cerevisiae Mre11͞ Rad50 protein complex also is linked to regulatory functions in the yeast cellular DNA damage response. Mutations in ScMRE11 suppress the inability of Yku70 mutants to overcome DSB-induced cell cycle arrest (9). Further, the response of Scrad50 mutants to hydroxyurea treatment suggests that the yeast Mre11͞Rad50 complex also may function in the activation of the S phase cell cycle checkpoint (10).Two recent observations link the human Mre11͞Rad50 complex to DSB recognition and the activation of cell cycle checkpoints. First, hMre11 lo...
BackgroundCaveolin-1 (Cav-1), the major component of caveolae, is a 21–24 kDa integral membrane protein that interacts with a number of signaling molecules. By acting as a scaffolding protein, Cav-1 plays crucial roles in the regulation of various physiologic and patho-physiologic processes including oncogenic transformation and tumorigenesis, and tumor invasion and metastasis.Methodology/Principal FindingsIn the present study we sought to explore the role of Cav-1 in response to DNA damage and the mechanism involved. We found that the level of Cav-1 was up-regulated rapidly in cells treated with ionizing radiation. The up-regulation of Cav-1 following DNA damage occurred only in cells expressing endogenous Cav-1, and was associated with the activation of DNA damage response pathways. Furthermore, we demonstrated that the expression of Cav-1 protected cells against DNA damage through modulating the activities of both the homologous recombination (HR) and non-homologous end joining (NHEJ) repair systems, as evidenced by the inhibitory effects of the Cav-1-targeted siRNA on cell survival, HR frequency, phosphorylation of DNA-dependent protein kinase (DNA-PK), and nuclear translocation of epidermal growth factor receptor (EGFR) following DNA damage, and by the stimulatory effect of the forced expression of Cav-1 on NHEJ frequency.Conclusion/SignificanceOur results indicate that Cav-1 may play a critical role in sensing genotoxic stress and in orchestrating the response of cells to DNA damage through regulating the important molecules involved in maintaining genomic integrity.
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