title: SCF(β-TRCP) promotes cell growth by targeting PR-Set7/Set8 for degradation.
abstract: The Set8/PR-Set7/KMT5a methyltransferase plays critical roles in governing transcriptional regulation, cell cycle progression and tumorigenesis. Although CRL4(Cdt2) 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 SCF(β-TRCP) earmarks Set8 for ubiquitination and degradation in a casein kinase I-dependent manner, which is activated by DNA-damaging agents. Biologically, both CRL4(Cdt2) and SCF(β-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.
authors.affiliation: The Cyrus Tang Hematology Center and Collaborative Innovation Center of Hematology, Jiangsu Institute of Hematology, the First Affiliated Hospital, Soochow University, Suzhou 215123, P.R. China.|Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA.
authors.forename: Zhiwei
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA.
authors.forename: Xiangpeng
authors.initials: X
authors.lastname: Dai
authors.affiliation: Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA.|Department of Pathology, Xinxiang Medical University, Xinxiang 453000, P.R. China.
authors.forename: Jiateng
authors.initials: J
authors.lastname: Zhong
authors.affiliation: Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Inuzuka
authors.affiliation: Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA.
authors.forename: Lixin
authors.initials: L
authors.lastname: Wan
authors.affiliation: Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA.|Department of Pathophysiology, Basic Medical College, Jilin University, Changchun 130021, P.R. China.
authors.forename: Xiaoning
authors.initials: X
authors.lastname: Li
authors.affiliation: The Cyrus Tang Hematology Center and Collaborative Innovation Center of Hematology, Jiangsu Institute of Hematology, the First Affiliated Hospital, Soochow University, Suzhou 215123, P.R. China.
authors.forename: Lixia
authors.initials: L
authors.lastname: Wang
authors.affiliation: The Cyrus Tang Hematology Center and Collaborative Innovation Center of Hematology, Jiangsu Institute of Hematology, the First Affiliated Hospital, Soochow University, Suzhou 215123, P.R. China.
authors.forename: Xiantao
authors.initials: X
authors.lastname: Ye
authors.affiliation: Department of Pathophysiology, Basic Medical College, Jilin University, Changchun 130021, P.R. China.
authors.forename: Liankun
authors.initials: L
authors.lastname: Sun
authors.affiliation: Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA.|State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yue-yang Road, Shanghai 200031, P.R. China.
authors.forename: Daming
authors.initials: D
authors.lastname: Gao
authors.affiliation: Department of Pathology, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts 02129, USA.
authors.forename: Lee
authors.initials: L
authors.lastname: Zou
authors.affiliation: Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA.
authors.forename: Wenyi
authors.initials: W
authors.lastname: Wei
mesh_terms: D002453:Cell Cycle / Q000502:physiology; D002455:Cell Division / Q000502:physiology; D002460:Cell Line; D005786:Gene Expression Regulation / Q000502:physiology*; D015971:Gene Expression Regulation, Enzymologic; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D044843:SKP Cullin F-Box Protein Ligases / Q000235:genetics / Q000378:metabolism*
chemical_list: D011495:Histone-Lysine N-Methyltransferase; C470730:KMT5A protein, human; D044843:SKP Cullin F-Box Protein Ligases