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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.

Pubmed ID: 19837670

Authors

  • Li DQ
  • Divijendra Natha Reddy S
  • Pakala SB
  • Wu X
  • Zhang Y
  • Rayala SK
  • Kumar R

Journal

The Journal of biological chemistry

Publication Data

December 11, 2009

Associated Grants

  • Agency: NCI NIH HHS, Id: CA98823
  • Agency: NCI NIH HHS, Id: CA98823-S1
  • Agency: NCI NIH HHS, Id: R01 CA127770

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