2. Academic Validation
  3. FBXW8-dependent degradation of MRFAP1 in anaphase controls mitotic cell death

FBXW8-dependent degradation of MRFAP1 in anaphase controls mitotic cell death

  • Oncotarget. 2017 Oct 12;8(57):97178-97186. doi: 10.18632/oncotarget.21843.
Duan-Zhuo Li 1,  Shun-Fang Liu 2,  Lan Zhu 3,  Yu-Xing Wang 1,  Yi-Xiang Chen 1,  Jie Liu 1,  Gang Hu 1,  Xin Yu 1,  Jian Li 4,  Jin Zhang 5,  Zhi-Xiang Wu 6,  Han Lu 7,  Wei Liu 3,  Bin Liu 1
Affiliations

Affiliations

  • 1 Hubei Key Laboratory for Kidney Disease Pathogenesis and Intervention, Huangshi Central Hospital of Edong Healthcare Group, Hubei Polytechnic University School of Medicine, Huangshi, Hubei 435003, PR China.
  • 2 Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, PR China.
  • 3 School of Molecular Sciences and Biodesign Center for Applied Structural Discovery, Biodesign Institute, Arizona State University, Tempe, AZ 85287, USA.
  • 4 Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY 40536, USA.
  • 5 School of Basic Medical Sciences, Nanchang University, Nanchang, Jiangxi 330031, PR China.
  • 6 Department of Pediatric Surgery, Xinhua Hospital, Shanghai Jiao-Tong University School of Medicine (SJTU-SM), Shanghai 200092, PR China.
  • 7 Department of Anesthesiology, Ruijin Hospital, Shanghai Jiao-Tong University School of Medicine (SJTU-SM), Shanghai 200025, PR China.
PMID: 29228602 DOI: 10.18632/oncotarget.21843
Abstract

Mof4 family associated protein 1 (MRFAP1) is a 14 kDa nuclear protein, which involves in maintaining normal histone modification levels by negatively regulating recruitment of the NuA4 (nucleosome acetyltransferase of H4) Histone Acetyltransferase complex to chromatin. MRFAP1 has been identified as one of the most up-regulated proteins after NEDD8 (neural precursor cell expressed developmentally down-regulated 8) inhibition in multiple human cell lines. However, the biological function of MRFAP1 and the E3 Ligase that targets MRFAP1 for destruction remain mysterious. Here we show, by using an immunoprecipitation-based proteomics screen, that MRFAP1 is an interactor of the F-box protein FBXW8. MRFAP1 is degraded by means of the ubiquitin Ligase Cul7/FBXW8 during mitotic anaphase-telophase transition and accumulated in mitotic metaphase. Overexpression of FBXW8 increased the polyubiquitination and decreased the stability of MRFAP1, whereas knockdown of FBXW8 prolonged the half-life of MRFAP1. Moreover, forced expression of MRFAP1 in HeLa cells caused growth retardation and genomic instability, leading to severe mitotic cell death. Thus, Cul7/FBXW8-mediated destruction of MRFAP1 is a regulatory component monitoring the anaphase-telophase transition and preventing genomic instability.

Keywords

FBXW8; MRFAP1; genomic instability; mitosis.

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