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Poly(ADP-ribosyl)ation of OVOL2 regulates aneuploidy and cell death in cancer cells.
Zhang, Rui; Hong, Jing-Jing; Yang, Qiaoyun; Ong, Chin-Tong; Li, Bo-An; Liou, Yih-Cherng.
Afiliación
  • Zhang R; Department of Biological Sciences, Faculty of Science, National University of Singapore, Singapore, 117543, Singapore.
  • Hong JJ; State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, 361005, Xiamen, Fujian, People's Republic of China.
  • Yang Q; Department of Biological Sciences, Faculty of Science, National University of Singapore, Singapore, 117543, Singapore.
  • Ong CT; Department of Biological Sciences, Faculty of Science, National University of Singapore, Singapore, 117543, Singapore.
  • Li BA; Temasek Life Sciences Laboratory, National University of Singapore, Singapore, 117604, Singapore.
  • Liou YC; State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, 361005, Xiamen, Fujian, People's Republic of China. bali@xmu.edu.cn.
Oncogene ; 38(15): 2750-2766, 2019 04.
Article en En | MEDLINE | ID: mdl-30542118
Poly(ADP-ribosyl)ation (PARylation) is a post-translational modification by which poly ADP-ribose (PAR) polymers are covalently added to proteins through a PAR polymerase (PARP). Here, using proteomic approach, we identify the transcriptional regulator, OVOL2, is a novel substrate of PARP1 and can be PARylated at residues Lysine 145, Lysine 176, and Lysine 212 within its C2H2 zinc finger domains. Overexpression of PARylated OVOL2 alters cell morphology and induces lagging chromosomes and aneuploidy. To define the underlying molecular mechanism by which OVOL2 induces abnormal cell cycle and centrosome amplification, we uncover that the OVOL2 elevates the protein levels of Cyclin E by enhancing its stability. Furthermore, we identify Skp2, the E3 ubiquitin ligase of Cyclin E, as a direct target of PARylated OVOL2. Using ChIP assay, the OVOL2 binding site on the promoter region of Skp2 is mapped. To further explore the physiological effect, we show that PARylated OVOL2 can induce cell death. Furthermore, to investigate PARylated OVOL2 function in vivo, we further develop a null-mice xenograft model and generate MMTV-PyVT transgenic mice and monitor the effect of wild-type OVOL2 and non-PARylated OVOL2-3K/A mutants on tumor progression. Consistently, overexpression of wild-type OVOL2 in both null-mice xenograft and MMTV-PyVT transgenic mice displays significantly reduction of tumor progression, respectively, further indicating that the function of OVOL2 as a tumor suppressor in vivo is highly regulated by PARylation. Taken together, our study sheds new light on PARP1-induced PARylation as a critical event in the OVOL2-mediated regulation of chromosomal integrity and suppression of cancer cells growth.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Poli Adenosina Difosfato Ribosa / Factores de Transcripción / Muerte Celular / Poli ADP Ribosilación Tipo de estudio: Prognostic_studies Límite: Animals / Female / Humans Idioma: En Revista: Oncogene Asunto de la revista: BIOLOGIA MOLECULAR / NEOPLASIAS Año: 2019 Tipo del documento: Article País de afiliación: Singapur Pais de publicación: Reino Unido
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Poli Adenosina Difosfato Ribosa / Factores de Transcripción / Muerte Celular / Poli ADP Ribosilación Tipo de estudio: Prognostic_studies Límite: Animals / Female / Humans Idioma: En Revista: Oncogene Asunto de la revista: BIOLOGIA MOLECULAR / NEOPLASIAS Año: 2019 Tipo del documento: Article País de afiliación: Singapur Pais de publicación: Reino Unido