MTA1 coregulator regulates p53 stability and function.
Although metastasis-associated protein 1 (MTA1) has recently been shown as a DNA damage responsive protein, the underlying mechanism for its role in DNA double-strand break (DSB) repair remains unknown. Here, we show that MTA1 controls p53 stability through inhibiting its ubiquitination by E3 ubiquitin ligases mouse double minute 2 (Mdm2) ... and constitutive photomorphogenic protein 1 (COP1). The underlying mechanisms involve the ability of MTA1 to compete with COP1 to bind to p53 and/or to destabilize COP1 and Mdm2. Consequently, MTA1 regulates the p53-dependent transcription of p53R2, a direct p53 target gene for supplying nucleotides to repair damaged DNA. Depletion of MTA1 impairs p53-dependent p53R2 transcription and compromises DNA repair. Interestingly, these events could be reversed by MTA1 reintroduction, indicating that MTA1 interjects into the p53-dependent DNA repair. Given the fact that MTA1 is widely up-regulated in human cancers, these findings in conjunction with our earlier finding of a crucial role of MTA1 in DSB repair suggest an inherent role of the MTA1-p53-p53R2 pathway in DNA damage response in cancer cells.
Mesh Terms:
Animals, Cell Line, Tumor, Cells, Cultured, DNA Damage, DNA Repair, Fibroblasts, Humans, Mice, Mice, Knockout, Nuclear Proteins, Proto-Oncogene Proteins c-mdm2, Recombinant Fusion Proteins, Transcription Factors, Tumor Suppressor Protein p53, Ubiquitin-Protein Ligases
Animals, Cell Line, Tumor, Cells, Cultured, DNA Damage, DNA Repair, Fibroblasts, Humans, Mice, Mice, Knockout, Nuclear Proteins, Proto-Oncogene Proteins c-mdm2, Recombinant Fusion Proteins, Transcription Factors, Tumor Suppressor Protein p53, Ubiquitin-Protein Ligases
J. Biol. Chem.
Date: Dec. 11, 2009
PubMed ID: 19837670
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