SCFFbxo22-KDM4A targets methylated p53 for degradation and regulates senescence

Yoshikazu Johmura, Jia Sun, Kyoko Kitagawa, Keiko Nakanishi, Toshiya Kuno, Aya Naiki-Ito, Yumi Sawada, Tomomi Miyamoto, Atsushi Okabe, Hiroyuki Aburatani, ShengFan Li, Ichiro Miyoshi, Satoru Takahashi, Masatoshi Kitagawa and Makoto Nakanishi ()
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Yoshikazu Johmura: Graduate School of Medical Sciences, Nagoya City University
Jia Sun: Graduate School of Medical Sciences, Nagoya City University
Kyoko Kitagawa: Hamamatsu University School of Medicine, Higashi-ku
Keiko Nakanishi: Aichi Human Service Center, Institute for Developmental Research
Toshiya Kuno: Graduate School of Medical Sciences, Nagoya City University
Aya Naiki-Ito: Graduate School of Medical Sciences, Nagoya City University
Yumi Sawada: Graduate School of Medical Sciences, Nagoya City University
Tomomi Miyamoto: Graduate School of Medical Sciences, Nagoya City University
Atsushi Okabe: Research Center for Advanced Science and Technology, The University of Tokyo
Hiroyuki Aburatani: Research Center for Advanced Science and Technology, The University of Tokyo
ShengFan Li: Zhongshan Hospital of Dalian University
Ichiro Miyoshi: Graduate School of Medical Sciences, Nagoya City University
Satoru Takahashi: Graduate School of Medical Sciences, Nagoya City University
Masatoshi Kitagawa: Hamamatsu University School of Medicine, Higashi-ku
Makoto Nakanishi: Graduate School of Medical Sciences, Nagoya City University

Nature Communications, 2016, vol. 7, issue 1, 1-12

Abstract: Abstract Recent evidence has revealed that senescence induction requires fine-tuned activation of p53, however, mechanisms underlying the regulation of p53 activity during senescence have not as yet been clearly established. We demonstrate here that SCFFbxo22-KDM4A is a senescence-associated E3 ligase targeting methylated p53 for degradation. We find that Fbxo22 is highly expressed in senescent cells in a p53-dependent manner, and that SCFFbxo22 ubiquitylated p53 and formed a complex with a lysine demethylase, KDM4A. Ectopic expression of a catalytic mutant of KDM4A stabilizes p53 and enhances p53 interaction with PHF20 in the presence of Fbxo22. SCFFbxo22-KDM4A is required for the induction of p16 and senescence-associated secretory phenotypes during the late phase of senescence. Fbxo22−/− mice are almost half the size of Fbxo22+/− mice owing to the accumulation of p53. These results indicate that SCFFbxo22-KDM4A is an E3 ubiquitin ligase that targets methylated p53 and regulates key senescent processes.

Date: 2016
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DOI: 10.1038/ncomms10574

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