SCFβ-TRCP promotes cell growth by targeting PR-Set7/Set8 for degradation

Zhiwei Wang (), Xiangpeng Dai, Jiateng Zhong, Hiroyuki Inuzuka, Lixin Wan, Xiaoning Li, Lixia Wang, Xiantao Ye, Liankun Sun, Daming Gao, Lee Zou and Wenyi Wei ()
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Zhiwei Wang: The Cyrus Tang Hematology Center and Collaborative Innovation Center of Hematology, Jiangsu Institute of Hematology, the First Affiliated Hospital, Soochow University
Xiangpeng Dai: Beth Israel Deaconess Medical Center, Harvard Medical School
Jiateng Zhong: Beth Israel Deaconess Medical Center, Harvard Medical School
Hiroyuki Inuzuka: Beth Israel Deaconess Medical Center, Harvard Medical School
Lixin Wan: Beth Israel Deaconess Medical Center, Harvard Medical School
Xiaoning Li: Beth Israel Deaconess Medical Center, Harvard Medical School
Lixia Wang: The Cyrus Tang Hematology Center and Collaborative Innovation Center of Hematology, Jiangsu Institute of Hematology, the First Affiliated Hospital, Soochow University
Xiantao Ye: The Cyrus Tang Hematology Center and Collaborative Innovation Center of Hematology, Jiangsu Institute of Hematology, the First Affiliated Hospital, Soochow University
Liankun Sun: Basic Medical College, Jilin University
Daming Gao: Beth Israel Deaconess Medical Center, Harvard Medical School
Lee Zou: Massachusetts General Hospital Cancer Center, Harvard Medical School
Wenyi Wei: Beth Israel Deaconess Medical Center, Harvard Medical School

Nature Communications, 2015, vol. 6, issue 1, 1-11

Abstract: Abstract The Set8/PR-Set7/KMT5a methyltransferase plays critical roles in governing transcriptional regulation, cell cycle progression and tumorigenesis. Although CRL4Cdt2 was reported to regulate Set8 stability, deleting the PIP motif only led to partial resistance to ultraviolet-induced degradation of Set8, indicating the existence of additional E3 ligase(s) controlling Set8 stability. Furthermore, it remains largely undefined how DNA damage-induced kinase cascades trigger the timely destruction of Set8 to govern tumorigenesis. Here, we report that SCFβ-TRCP earmarks Set8 for ubiquitination and degradation in a casein kinase I-dependent manner, which is activated by DNA-damaging agents. Biologically, both CRL4Cdt2 and SCFβ-TRCP-mediated pathways contribute to ultraviolet-induced Set8 degradation to control cell cycle progression, governing the onset of DNA damage-induced checkpoints. Therefore, like many critical cell cycle regulators including p21 and Cdt1, we uncover a tight regulatory network to accurately control Set8 abundance. Our studies further suggest that aberrancies in this delicate degradation pathway might contribute to aberrant elevation of Set8 in human tumours.

Date: 2015
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DOI: 10.1038/ncomms10185

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