Role for 53BP1 Tudor domain recognition of p53 dimethylated at lysine 382 in DNA damage signaling.
Modification of histone proteins by lysine methylation is a principal chromatin regulatory mechanism (Shi, Y., and Whetstine, J. R. (2007) Mol. Cell 25, 1-14). Recently, lysine methylation has been shown also to play a role in regulating non-histone proteins, including the tumor suppressor protein p53 (Huang, J., and Berger, S. L. (2008) Curr. Opin. Genet. Dev. 18, 152-158). Here, we identify a novel p53 species that is dimethylated at lysine 382 (p53K382me2) and show that the tandem Tudor domain of the DNA damage response mediator 53BP1 acts as an "effector" for this mark. We demonstrate that the 53BP1 tandem Tudor domain recognizes p53K382me2 with a selectivity relative to several other protein lysine methylation sites and saturation states. p53K382me2 levels increase with DNA damage, and recognition of this modification by 53BP1 facilitates an interaction between p53 and 53BP1. The generation of p53K382me2 promotes the accumulation of p53 protein that occurs upon DNA damage, and this increase in p53 levels requires 53BP1. Taken together, our study identifies a novel p53 modification, demonstrates a new effector function for the 53BP1 tandem Tudor domain, and provides insight into how DNA damage signals are transduced to stabilize p53.
Department of Biology, Stanford University, Stanford, California 94305, USA.
Ioulia
I
Kachirskaia
Xiaobing
X
Shi
Hiroshi
H
Yamaguchi
Kan
K
Tanoue
Hong
H
Wen
Evelyn W
EW
Wang
Ettore
E
Appella
Or
O
Gozani
D000595:Amino Acid Sequence; D004247:DNA / Q000737:chemistry; D004249:DNA Damage; D006657:Histones / Q000737:chemistry; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry* / Q000502:physiology*; D008239:Lysine / Q000737:chemistry; D008745:Methylation; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry; D017434:Protein Structure, Tertiary; D015398:Signal Transduction; D013379:Substrate Specificity; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry*; D000071857:Tumor Suppressor p53-Binding Protein 1
D006657:Histones; D047908:Intracellular Signaling Peptides and Proteins; D010455:Peptides; C495901:TP53 protein, human; C498301:TP53BP1 protein, human; D016159:Tumor Suppressor Protein p53; D000071857:Tumor Suppressor p53-Binding Protein 1; D004247:DNA; D008239:Lysine