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

Duan-Zhuo Li1, Shun-Fang Liu2, Lan Zhu3

  • 1Hubei 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.

Oncotarget
|December 13, 2017
PubMed

Insights

Mof4 family associated protein 1 (MRFAP1) is degraded by the Cul7/FBXW8 ubiquitin ligase during mitosis. This process is crucial for preventing genomic instability and ensuring proper cell cycle progression.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Genetics

Background:

  • Mof4 family associated protein 1 (MRFAP1) regulates histone modification by controlling the NuA4 complex.
  • MRFAP1 levels increase upon inhibition of NEDD8 (neural precursor cell expressed developmentally down-regulated 8).
  • The precise biological role of MRFAP1 and its regulatory E3 ligase were previously unknown.

Purpose of the Study:

  • To identify the E3 ligase responsible for MRFAP1 degradation.
  • To elucidate the role of MRFAP1 regulation in cell cycle control and genomic stability.

Main Methods:

  • Immunoprecipitation-based proteomics screen to identify MRFAP1 interactors.
  • Ubiquitination assays and Western blotting to assess MRFAP1 stability and polyubiquitination.
  • Cell-based assays in HeLa cells to evaluate the impact of MRFAP1 overexpression and FBXW8 modulation on cell growth and mitosis.

Main Results:

  • MRFAP1 interacts with the F-box protein FBXW8.
  • The Cul7/FBXW8 ubiquitin ligase complex targets MRFAP1 for degradation during mitotic anaphase-telophase transition.
  • FBXW8 overexpression enhances MRFAP1 polyubiquitination and reduces its stability, while FBXW8 knockdown prolongs MRFAP1 half-life.
  • MRFAP1 accumulation during metaphase is observed.
  • Forced expression of MRFAP1 leads to growth retardation, genomic instability, and mitotic cell death.

Conclusions:

  • Cul7/FBXW8-mediated degradation of MRFAP1 is a critical regulatory mechanism.
  • This pathway monitors the anaphase-telophase transition.
  • The degradation of MRFAP1 by Cul7/FBXW8 prevents genomic instability.
Keywords:
FBXW8MRFAP1genomic instabilitymitosis

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