The Role of Proteasome Chemical Inhibitors in Investigating the Mechanisms of Aneuploidy in Mammalian Oocytes

John   B.   Mailhes

Abstract

Very little is known about the numerous causes and molecular mechanisms of aneuploidy in any cell type. However, recent data suggest that alterations in proteasome activity may be one of several potential mechanisms that predispose cells to faulty chromosome segregation. Proteasomes represent multicatalytic 26S proteases consisting of a 20S central catalytic core bordered by two 19 S components that hydrolyze the Cterminal peptide bonds to acidic, basic, and hydrophobic amino acid residues of unwanted proteins in eukaryotic cells. Key cell-cycle regulatory proteins such as cyclins, cyclin-dependent kinase inhibitors, and anaphase-inhibitory proteins that have been ubiquinated by the anaphase promoting complex are subject to degradation by proteasomes. An association between proteasomes and chromosome segregation exists because proteasomes are responsible for proteolyzing subunits of the securin-cohesin protein complex which helps bind homologues together prior to meiotic anaphase I and sister chromatids during meiosis II and mitosis. This association suggests that if cohesins are not timely removed from chromosomes at anaphase onset, the probability of abnormal chromosome segregation will be increased. Recent data obtained from fission yeast and rodent cells exposed to proteasome inhibitors have revealed that faulty proteasome activity can lead to aberrant chromosome segregation. Certain peptide aldehydes that function as transition-state analogues can readily enter cells and inhibit 26S proteasome activity. The ability to alter the function of the proteasome/ubiquitin pathway in regulating cell-cycle control, chromosome segregation, and apoptosis provides a venue for addressing aneuploidy and underlies the current interest in the use of proteasome inhibitors as chemotherapeutic agents.

Keywords: proteasome, oocyte, chromosome, aneuploidy, cell cycle, phosphatase, kinase, cohesion complex, chromosome segregation, metaphase-anaphase transition