Prevention and Correction Mechanisms behind Anaphase Synchrony: Implications for the Genesis of Aneuploidy

Abstract

The perpetuation of the species' genomic identity strongly depends on the accurate maintenance of chromosome number through countless cell generations. The synchronous entry and progression of all chromosomes through anaphase is fundamental for the quality of mitosis and is guaranteed by error prevention and correction mechanisms that ultimately certify the bipolar attachment of chromosomes to the mitotic spindle, the uniform distribution of forces amongst different chromosomes, and the simultaneity of sister-chromatid separation. The existence of a kinetochore-attachment checkpoint (KAC; also known as spindle-assembly checkpoint) ensures a delay in anaphase onset if any kinetochore remains unattached or devoid of a proper complement of microtubules. The stochastic nature of micro tubule-kinetochore interactions predisposes the mitotic process to mistakes, but different molecular players cooperate by detecting and releasing incorrect attachments and thus delaying checkpoint satisfaction. Conversely, correct microtubule-kinetochore interactions become selectively stabilized. Once anaphase onset is triggered, the segregation velocities achieved by each chromosome should be similar, so that none of the chromosomes is lagged behind. This reflects the uniformity of forces acting on the different chromosomes and relies on a conspicuous mitotic spindle property known as microtubule poleward flux. Importantly, not all incorrect attachments are detected and resolved prior to anaphase leading to asynchronous chromosome segregation, but several mechanisms are in place to prevent aneuploidy. One of these mechanisms relies on anaphase spindle forces and another, known as the NoCut checkpoint, delays cell cleavage during cytokinesis until chromosomes can free the spindle mid-region. In this review we discuss how these different mechanisms act in concert to ensure the fidelity of the mitotic process. Copyright (C) 2011 S. Karger AG, Basel