Abstract
PHF20 is a multidomain protein and subunit of a lysine acetyltransferase complex that acetylates histone H4 and p53 but whose function is unclear. Using biochemical, biophysical and cellular approaches, we determined that PHF20 is a direct regulator of p53. A Tudor domain in PHF20 recognized p53 dimethylated at Lys370 or Lys382 and a homodimeric form of this Tudor domain could associate with the two dimethylated sites on p53 with enhanced affinity, indicating a multivalent interaction. Association with PHF20 promotes stabilization and activation of p53 by diminishing Mdm2-mediated p53 ubiquitylation and degradation. PHF20 contributes to upregulation of p53 in response to DNA damage, and ectopic expression of PHF20 in different cell lines leads to phenotypic changes that are hallmarks of p53 activation. Overall our work establishes that PHF20 functions as an effector of p53 methylation that stabilizes and activates p53.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 916-924 |
| Number of pages | 9 |
| Journal | Nature Structural and Molecular Biology |
| Volume | 19 |
| Issue number | 9 |
| DOIs | |
| State | Published - Sep 2012 |
| Externally published | Yes |
Bibliographical note
Funding Information:We acknowledge the use of beamline 19-BM at the Advanced Photon Source (APS), Argonne National Laboratory. APS is operated by UChicago Argonne, LLC, for the US Department of Energy under contract DE-AC02-06CH11357. We are grateful to Y. Kim at APS for assistance with X-ray data collection. We acknowledge the help of A. Espejo and C. Sagum with protein microarray work and the support from the Center for Environmental and Molecular Carcinogenesis at M.D. Anderson Cancer Center. This research is supported by US National Institutes of Health (NIH) grant CA132878 (G.M.), NIH grant CA137041 and James and Esther King grant 1KG02 (J.Q.C.), institutional NIH grant ES007784 and Cancer Prevention Research Institute of Texas grant RP110471 (M.T.B.) and NIH training grant 5T32ES007247 (A.I.B.).
