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.
Li
Da-Qiang
DQ
Department of Biochemistry and Molecular Biology and Institute of Coregulator Biology, The George Washington University Medical Center, Washington, DC 20037, USA.
Divijendra Natha Reddy
Sirigiri
S
Pakala
Suresh B
SB
Wu
Xifeng
X
Zhang
Yanping
Y
Rayala
Suresh K
SK
Kumar
Rakesh
R
D000818:Animals; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D004249:DNA Damage; D004260:DNA Repair; D005347:Fibroblasts / Q000166:cytology / Q000502:physiology; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins; D015534:Trans-Activators; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism
C503336:Mta1 protein, mouse; D009687:Nuclear Proteins; D011993:Recombinant Fusion Proteins; D012097:Repressor Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; C471982:COP1 protein, mouse; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2; D044767:Ubiquitin-Protein Ligases