p53 is regulated by the lysine demethylase LSD1.
p53, the tumour suppressor and transcriptional activator, is regulated by numerous post-translational modifications, including lysine methylation. Histone lysine methylation has recently been shown to be reversible; however, it is not known whether non-histone proteins are substrates for demethylation. Here we show that, in human cells, the histone lysine-specific demethylase LSD1 (refs 3, 4) interacts with p53 to repress p53-mediated transcriptional activation and to inhibit the role of p53 in promoting apoptosis. We find that, in vitro, LSD1 removes both monomethylation (K370me1) and dimethylation (K370me2) at K370, a previously identified Smyd2-dependent monomethylation site. However, in vivo, LSD1 shows a strong preference to reverse K370me2, which is performed by a distinct, but unknown, methyltransferase. Our results indicate that K370me2 has a different role in regulating p53 from that of K370me1: K370me1 represses p53 function, whereas K370me2 promotes association with the coactivator 53BP1 (p53-binding protein 1) through tandem Tudor domains in 53BP1. Further, LSD1 represses p53 function through the inhibition of interaction of p53 with 53BP1. These observations show that p53 is dynamically regulated by lysine methylation and demethylation and that the methylation status at a single lysine residue confers distinct regulatory output. Lysine methylation therefore provides similar regulatory complexity for non-histone proteins and for histones.
Huang
Jing
J
The Wistar Institute, 3601 Spruce Street, Philadelphia, Pennsylvania 19104, USA.
Sengupta
Roopsha
R
Espejo
Alexsandra B
AB
Lee
Min Gyu
MG
Dorsey
Jean A
JA
Richter
Mario
M
Opravil
Susanne
S
Shiekhattar
Ramin
R
Bedford
Mark T
MT
Jenuwein
Thomas
T
Berger
Shelley L
SL
D017209:Apoptosis; D002460:Cell Line; D056466:Histone Demethylases; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D008745:Methylation; D010089:Oxidoreductases, N-Demethylating / Q000378:metabolism*; D011485:Protein Binding; D015533:Transcriptional Activation; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D000071857:Tumor Suppressor p53-Binding Protein 1