MTA1 Coregulator Regulates p53 Stability and Function

• Published in: The Journal of biological chemistry Vol. 284; no. 50; pp. 34545 - 34552
• Main Authors: Li, Da-Qiang, Divijendra Natha Reddy, Sirigiri, Pakala, Suresh B., Wu, Xifeng, Zhang, Yanping, Rayala, Suresh K., Kumar, Rakesh
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 11.12.2009; American Society for Biochemistry and Molecular Biology
• Subjects: Animals; Cell Line, Tumor; Cells, Cultured; DNA Damage; DNA Repair; Fibroblasts - cytology; Fibroblasts - physiology; Humans; Mechanisms of Signal Transduction; Mice; Mice, Knockout; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Proto-Oncogene Proteins c-mdm2 - genetics; Proto-Oncogene Proteins c-mdm2 - metabolism; Recombinant Fusion Proteins - genetics; Recombinant Fusion Proteins - metabolism; Repressor Proteins; Trans-Activators; Transcription Factors - genetics; Transcription Factors - metabolism; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism; Ubiquitin-Protein Ligases - genetics; Ubiquitin-Protein Ligases - metabolism
• ISSN: 0021-9258; 1083-351X; 1083-351X
• DOI: 10.1074/jbc.M109.056499

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.