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MLL/WDR5 complex recruits centriolar satellite protein Cep72 to regulate microtubule nucleation and spindle formation

Swathi Chodisetty1,2, Aditi Arora1,3, Kausika Kumar Malik1

  • 1Laboratory of Cell Cycle Regulation, Centre for DNA Fingerprinting and Diagnostics (CDFD), Hyderabad 500039, India.

Science Advances
|December 11, 2024
PubMed

Insights

The mixed-lineage leukemia (MLL) protein is crucial for microtubule organization at the centrosome. Loss of MLL/WDR5 impacts cell division and chromosome alignment, revealing a new role for MLL in neurodevelopmental disorders.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Genetics

Background:

  • Centrosome dysfunction is linked to microcephaly.
  • Mixed-lineage leukemia (MLL/KMT2A) haploinsufficiency causes Wiedemann-Steiner syndrome (WSS), a neurodevelopmental disorder with microcephaly.
  • The precise function of MLL at the centrosome remains unclear.

Purpose of the Study:

  • To investigate the role of the MLL/WDR5 complex at the centrosome.
  • To determine how MLL/WDR5 influences microtubule organization and centrosome function.
  • To elucidate the mechanism of Cep72 recruitment to the centrosome by MLL/WDR5.

Main Methods:

  • Analysis of microtubule nucleation and regrowth in cells lacking MLL/WDR5.
  • Immunolocalization studies to determine the subcellular localization of MLL/WDR5, Cep72, and γ-TuRCs.
  • Assessment of spindle formation and chromosome alignment during mitosis in MLL/WDR5-deficient cells.
  • Biochemical assays to confirm the interaction between MLL/WDR5 and Cep72.

Main Results:

  • Loss of MLL/WDR5 impairs microtubule nucleation and regrowth.
  • MLL/WDR5 localize to the pericentriolar material and interact with Cep72 and γ-TuRCs.
  • MLL/WDR5 promote the centrosomal localization of γ-TuRCs and AKAP9, a phenotype seen in WSS patient cells.
  • Absence of MLL, WDR5, or Cep72 disrupts spindle formation and causes chromosome misalignment.
  • MLL and WDR5 are essential for recruiting Cep72 to the centrosome.

Conclusions:

  • MLL has a previously unrecognized function at the centrosome, regulating microtubule organization.
  • The MLL/WDR5 complex is vital for proper centrosome function and mitotic progression.
  • MLL/WDR5-mediated recruitment of Cep72 to the centrosome is a key mechanism in maintaining genomic stability and normal development.

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