Office of Technology Transfer – University of Michigan

A Genetically Encoded Activator and Controller of the Mitotic Checkpoint

Technology #6745

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Researchers
Ajit P. Joglekar
Managed By
Ed Pagani
Assistant Director, Health Technologies 734-763-3558
Patent Protection
US Patent Pending 2017-0137478
Publications
The kinetochore encodes a mechanical switch to disrupt spindle assembly checkpoint signalling.
Nat Cell Biol. 2015 Jul;17(7):868-79. doi: 10.1038/ncb3179. Epub 2015 Jun 8., 2015

Spontaneous abortion or miscarriage is a pregnancy that is not viable or in which the fetus is born before the 20th week of pregnancy. Spontaneous abortions occur in 15-20% of recognized pregnancies, with 1% of women having 3 or more consecutive miscarriages. Female fertility is decreased with advanced maternal age, with the risk of miscarriages increasing up to 75% among women aged over 40 years. Chromosomal segregation errors are the most common cause of spontaneous abortion, reported as occurring in up to 60% of all miscarriages. There are no preventative therapeutics for spontaneous abortions.

The formation of sperm or eggs (haploid gametes) requires a form of cell division known as meiosis in which DNA replication is followed by two rounds of cell divisions. The spindle assembly checkpoint (SAC) is a key regulator of meiosis and delays cell division until all chromatids are properly attached to microtubules to ensure that proper chromosome segregation occurs. Proteins and transcripts of SAC components have decreased expression with maternal aging, and are thought to contribute to increased rates of chromosomal segregation errors and miscarriage.

Stabilization of SAC through Mps1 and Spc105 ensures proper chromosome segregation

Within unattached chromatids, the Mps1 kinase enables the recruitment of SAC proteins to stall the cell cycle. The phosphorylation of the protein Spc105 by Mps1 has been identified as necessary and sufficient to initiate the SAC cascade for cell cycle arrest. Exogenously activating SAC by inducing the dimerization of engineered fragments of Mps1 and Spc105 has been proposed as a method to strengthen SAC to control the duration of the cell cycle. This tunable SAC activator will provide additional time for proper chromosome segregation to prevent segregation errors during female meiosis.

Applications

  • Therapeutic for miscarriage prevention
  • Therapeutic for cell division disorders

Advantages

  • Specific targeting of SAC
  • Tunable delay and activation of cell cycle
  • Maximize chromosome segregation accuracy