Enhanced genomic instabilities caused by deregulated microtubule dynamics and chromosome segregation: a perspective from genetic studies in mice

Abstract

Aneuploidy is defined as numerical abnormalities of chromosomes and is frequently (>90%) present in solid tumors. In general, tumor cells become increasingly aneuploid with tumor progression. It has been proposed that enhanced genomic instability at least contributes significantly to, if not requires, tumor progression. Two major modes for genomic instability are microsatellite instability (MIN) and chromosome instability (CIN). MIN is associated with DNA-level defects (e.g. mismatch repair defects), and CIN is associated with mitotic errors such as chromosome mis-segregation. The mitotic spindle assembly checkpoint (SAC) ensures that cells with defective mitotic spindles or defective interaction between the spindles and kinetochores do not initiate chromosomal segregation during mitosis. Thus, the SAC functions to protect the cell from chromosome mis-segregation and anueploidy during cell division. A loss of the SAC function results in gross aneuploidy, a condition from which cells with an advantage for proliferation will be selected. During the past several years, a flurry of genetic studies in mice and humans strongly support the notion that an impaired SAC causes enhanced genomic instabilities and tumor development. This review article summarizes the roles of key spindle checkpoint proteins {i.e. Mad1/Mad1L1, Mad2/Mad2L1, BubR1/Bub1B, Bub3/Bub3 [conventional protein name (yeast or human)/mouse protein name]} and the modulators (i.e. Chfr/Chfr, Rae1/Rae1, Nup98/Nup98, Cenp-E/CenpE, Apc/Apc) in genomic stability and suppression of tumor development, with a focus on information from genetically engineered mouse model systems. Further elucidation of molecular mechanisms of the SAC signaling has the potential for identifying new targets for rational anticancer drug design.

Fig. 1.

Regulations on mitotic metaphase–anaphase transition through SAC and APC/C. Mitotic unattached kinetochores are critical structures in mitotic regulations. They serve as a scaffold for mitotic regulatory signaling proteins including SAC proteins, and the enriched localization of signaling proteins is thought to be important for proper SAC function. Encircled by bold line are the proteins discussed in text. Mps1 is an SAC kinase. CENP-E is a mitotic motor whose inactivation abrogates SAC function. Bub3 binds to BubR1 kinase, both are core SAC components. Mad1 is an SAC component and catalytically converts Mad2 three dimensional structure from open [Mad2(o)] to closed [Mad2(c)] form. The closed form Mad2(c) makes a part of the SAC inhibitory complex. The SAC inhibitory complex binds to a ubiquitin ligase APC/C and inhibits the activity. Once SAC-mediated inhibition is released, the APC/C polyubiquitylates its mitotic targets, e.g. Cyclin B and Securin, and leads them to proteasome-dependent degradation. Separase is a protease that degrades cohesins. Cohesins hold sister chromatids together. Sgo1 protects cohesins from premature degradation through physical association. TAO1 (One thousand and one amino acids) is an SAC kinase that aids Mad1–Mad2 interaction. Plk1 is a mitotic kinase whose inactivation abrogates Mad1 and Mad2 localization to kinetochores. Plk 1 interacting checkpoint helicase (PICH) is required for Mad1–Mad2 interaction. Chfr localizes on mitotic spindles. Apc interacts with EB1 and localizes on plus end of microtubules. Rae1–Nup98 complex, which is a part of nuclear pore complex during interphase and breaks into subcomplex during mitosis, inhibits premature securin degradation through interaction with APC/C during early mitosis.