Mechanisms to Avoid and Correct Erroneous Kinetochore-Microtubule Attachments

Abstract

In dividing vertebrate cells multiple microtubules must connect to mitotic kinetochores in a highly stereotypical manner, with each sister kinetochore forming microtubule attachments to only one spindle pole. The exact sequence of events by which this goal is achieved varies considerably from cell to cell because of the variable locations of kinetochores and spindle poles, and randomness of initial microtubule attachments. These chance encounters with the kinetochores nonetheless ultimately lead to the desired outcome with high fidelity and in a limited time frame, providing one of the most startling examples of biological self-organization. This chapter discusses mechanisms that contribute to accurate chromosome segregation by helping dividing cells to avoid and resolve improper microtubule attachments.

A Molecular View of Kinetochore Assembly and Function

“…This property of kinetochores is generally referred to as error correction, and its molecular basis remains rather poorly understood. The pioneering experiments of Nicklas and colleagues [10], as well as more recent functional analyses [11,12,13], suggest that the development of tension within the kinetochore or between sister kinetochores contributes to discerning correct attachment from incorrect ones (see chapter by Lampson and Grishchuk, reference [14]). Kinetochores also regulate the spindle assembly checkpoint (SAC, also named the metaphase checkpoint), a feedback mechanism required to couple the initiation of mitotic exit with the completion of sister chromatid bi-orientation [15,16].…”

“…Below, we first present a brief summary of studies on the centromere and its epigenetic definition. We then review progress toward defining the structural organization of kinetochores, with references to older foundational work and to accompanying chapters in this issue that focus on the functional output of kinetochores, including microtubule-dependent force generation, error correction, and the SAC (see references [14,17,30]). In our discussion of kinetochore structural organization, we will focus on human kinetochores and lessons from recent biochemical reconstitution efforts but will refer to work in other models to highlight important parallels/differences, and also to present questions that emerge from cross-model comparisons.…”

“…Aurora B kinase, a major regulator of kinetochore-microtubule attachment [14], phosphorylates up to nine sites in the human Ndc80 N-terminal tail [213,216,218,221,222,224,225,226,229,233]. Phosphorylation neutralizes the intrinsic positive charge of the Ndc80 N-terminal domain, greatly decreasing the binding affinity of the Ndc80 complex for microtubules in vitro [209,216,218,225,226].…”

How Kinetochore Architecture Shapes the Mechanisms of Its Function

“…Although bipolar attachment of sister kinetochores to microtubules emanating from opposite spindle poles is strongly favored, two types of erroneous attachments occur frequently: merotelic and monopolar [57, 92, 93]. The first type of erroneous attachments is known as merotelic attachment, wherein a single kinetochore attaches to microtubules emanating from both poles.…”

“…Potential mechanisms that can explain this error correction process have been discussed in excellent reviews (e.g. see [92, 96]). Therefore, we will only describe the prevalent model, and focus on the potential role of kinetochore architecture in the error correction process.…”