MTA1 Coregulator Regulates p53 Stability and Function

Da-Qiang Li,Sirigiri Divijendra Natha Reddy,Suresh B Pakala,Xifeng Wu,Yanping Zhang,Suresh K Rayala,Rakesh Kumar

doi:10.1074/jbc.m109.056499

Abstract

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.

Highlights

The p53 tumor suppressor is a central component of cellular mechanisms that respond to DNA damage signals to preserve genomic integrity [1, 2]
These findings in conjunction with our earlier finding of a crucial role of metastasis-associated protein 1 (MTA1) in double-strand break (DSB) repair suggest that MTA1 is a potential therapeutic target that could be used to enhance the effectiveness of ionizing radiation (IR) or DNA-damaging anticancer agents in cancer cells by targeting MTA1 expression
To further identify the regions of p53 involved in binding MTA1, we used a series of glutathione Stransferase (GST)-p53 fusion proteins [38] and analyzed their ability to bind to 35S-labeled, in vitro-translated, full-length MTA1

Summary

Introduction

The p53 tumor suppressor is a central component of cellular mechanisms that respond to DNA damage signals to preserve genomic integrity [1, 2]. Using a variety of genetic, biochemical, and molecular approaches, we show that MTA1 is a direct stabilizer of the p53 protein by inhibiting its ubiquitination by E3 ligases, and regulates p53-dependent function in DNA repair.

Results

Conclusion