Detection and Correction of Merotelic Kinetochore Orientation by Aurora B and its Partners

Abstract

Merotelic kinetochore orientation is a kinetochore-microtubule mis-attachment in which a single kinetochore binds microtubules to both spindle poles, rather than just one. Merotelic attachments occur frequently in early mitosis and can induce anaphase lagging chromosomes and aneuploidy if not corrected before anaphase onset. Merotelic kinetochore orientation does not interfere with chromosome alignment at the metaphase plate and does not activate the mitotic spindle checkpoint. However, a correction mechanism for merotelic attachment reduces the number of merotelic kinetochores entering anaphase, thus preventing chromosome mis-segregation. Results from many different studies support the idea that Aurora B kinase plays a critical role in this merotelic correction mechanism by phosphorylating key substrates at the kinetochore and promoting turnover of kinetochore microtubules. In addition, recent studies are starting to identify the possible 'sensors' of the system that would be able to detect the mis-attachment and communicate this to Aurora B. Here, I review these studies and discuss a model for how merotelic kinetochore orientation could be detected and corrected before anaphase onset.

DNA Topoisomerase II Is a Determinant of the Tensile Properties of Yeast Centromeric Chromatin and the Tension Checkpoint

“…Ipl1/Aurora-B could be coupled to CEN deformation in a variety of ways. In one model, stretching of CEN fibers and/or components of the kinetochore under tension has been proposed to separate Ipl1/Aurora-B within the inner CEN from the kinetochore substrates in- volved in detachment (Tanaka et al, 2002;Cimini, 2007). Overall, these considerations suggest the mechanical resistance of CEN chromatin to deformation could be an important parameter influencing the activity of error correction mechanisms.…”

“…With the exception of merotelic interactions (Cimini, 2007), those attachments that are targeted for error correction generally tend to be characterized by a reduction in the mechanical tension generated by pulling bioriented kinetochores toward opposite spindle poles. Ipl1/Aurora-B has thus been suggested to control a tension checkpoint, implying a mechanism to monitor tension (Biggins and Murray, 2001).…”

Modeling the temporal evolution of the spindle assembly checkpoint and role of Aurora B kinase

“…One further type of attachment (monotelic) is common in the very early stages of prometaphase. However, they exist only as brief, transitory states in the subsequent attachment process (37)(38)(39). Therefore, we do not consider them further.…”

“…Subsequently, the incorrect attachments are released via the action of Aurora B kinase (14,15) and, after relocating to the metaphase plate, it is common that this kinetochore pair form amphitelic attachments (38). Merotelically attached kinetochores are aligned at the spindle equator, where Aurora B destabilizes the aberrant attachments, thus allowing the resultant pair of sister kinetochores to almost immediately become amphitelically attached (37).…”

“…We assume that both kinetochores within the unit have all their binding sites occupied or both kinetochores have binding sites available (37)(38)(39). We assume further that these 2 sets can be divided as follows: a unit displaying full occupancy can be in either a merotelic (ME) or amphitelic (C) state; otherwise it is deemed to be in a syntelic (S) or unattached (U) state (37)(38)(39). Following the above arguments a unit state transition network can be constructed (see Fig.…”