2. Academic Validation
  3. Phosphorylation at Ser68 facilitates DCAF11-mediated ubiquitination and degradation of CENP-A during the cell cycle

Phosphorylation at Ser68 facilitates DCAF11-mediated ubiquitination and degradation of CENP-A during the cell cycle

  • Cell Rep. 2021 Nov 9;37(6):109987. doi: 10.1016/j.celrep.2021.109987.
Kehui Wang 1,  Yuting Liu 2,  Zhouliang Yu 2,  Bo Gu 3,  Jie Hu 2,  Li Huang 1,  Xiao Ge 4,  Lingyi Xu 5,  Mengyu Zhang 6,  Jicheng Zhao 1,  Mingli Hu 2,  Rongrong Le 7,  Qiang Wu 4,  Sheng Ye 8,  Shaorong Gao 7,  Xiaodong Zhang 3,  Rui-Ming Xu 2,  Guohong Li 9
Affiliations

Affiliations

  • 1 National Laboratory of Bio-macromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Science, Beijing 100101, China.
  • 2 National Laboratory of Bio-macromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Science, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China.
  • 3 College of Life Sciences, Wuhan University, Wuhan 430072, China.
  • 4 Center for Comparative Biomedicine, Key Laboratory of Systems Biomedicine (Ministry of Education), Institute of Systems Biomedicine, Shanghai Jiao Tong University, Shanghai 200240, China.
  • 5 Department of Biophysics, Department of Pathology of Sir Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China; Department of Biophysics, Institute of Neuroscience, NHC and CAMS Key Laboratory of Medical Neurobiology, Zhejiang University School of Medicine, Hangzhou 310058, China.
  • 6 Tianjin Key Laboratory of Function and Application of Biological Macromolecular Structures, School of Life Sciences, Tianjin University, 92 Weijin Road, Nankai District, Tianjin 300072, China.
  • 7 School of Life Sciences and Technology, Tongji University, Shanghai 200092, China.
  • 8 Tianjin Key Laboratory of Function and Application of Biological Macromolecular Structures, School of Life Sciences, Tianjin University, 92 Weijin Road, Nankai District, Tianjin 300072, China; Life Sciences Institute, Zhejiang University, Hangzhou 310058, China.
  • 9 National Laboratory of Bio-macromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Science, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China. Electronic address: [email protected].
PMID: 34758320 DOI: 10.1016/j.celrep.2021.109987
Abstract

CENP-A (centromeric protein A), a histone H3 variant, specifies centromere identity and is essential to centromere maintenance. Little is known about how protein levels of CENP-A are controlled in mammalian cells. Here, we report that the phosphorylation of CENP-A Ser68 primes the ubiquitin-proteasome-mediated proteolysis of CENP-A during mitotic phase in human cultured cells. We identify two major polyubiquitination sites that are responsible for this phosphorylation-dependent degradation. Substituting the two residues, Lys49 and Lys124, with arginines abrogates proper CENP-A degradation and results in CENP-A mislocalization to non-centromeric regions. Furthermore, we find that DCAF11 (DDB1 and CUL4 associated factor 11/WDR23) is the E3 Ligase that specifically mediates the observed polyubiquitination. Deletion of DCAF11 hampers CENP-A degradation and causes its mislocalization. We conclude that the Ser68 phosphorylation plays an important role in regulating cellular CENP-A homeostasis via DCAF11-mediated degradation to prevent ectopic localization of CENP-A during the cell cycle.

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