Monitoring Kinetochore-Microtubule Attachment
Chromosomes segregate properly during mitotic anaphase if sister kinetochores are connected to the opposite poles. A control mechanism, called the spindle assembly checkpoint (SAC), prevents anaphase until all chromosomes are properly attached (Musacchio and Salmon, 2007). In bipolar attachment, often termed amphitelic, pulling forces acting on kinetochores by microtubules emanating from the opposite poles counteract cohesion between sister kinetochores. Thus tension between sister kinetochores is generated. Once all sister kinetochores are under tension, the SAC is silenced, leading to anaphase. Defects in SAC signalling in vertebrates usually result in lagging chromosomes and, in consequence, accumulation of aneuploidy (Kops et al., 2005). Fully functional SAC, however, is not essential in flies (Buffin et al., 2007).
After nuclear envelope breakdown, kinetochores are initially unattached, which activates the SAC, though even a single unattached kinetochore may block anaphase by SAC activity (Rieder et al., 1995; Musacchio and Salmon, 2007). As microtubules penetrate the cytoplasm, the attachments between microtubules and kinetochores are often by chance, hence commonly erroneous (Cimini et al., 2003). Both sister kinetochores may attach to the same pole (monopolar attachement), which is called the syntely. Syntely results in lack of tension between sister kinetochores, a condition delaying anaphase (Nicklas et al., 1995). In situation when one sister kinetochore is attached to one pole and the second sister kinetochore is attached to two opposite poles, the type of attachment is called the merotely. Despite incorrect attachment, tension is generated and SAC does not sense such an error (Cimini et al., 2002).
The delay of anaphase is triggered by a diffusible signal elicited by SAC activation at the kinetochore (Musacchio and Salmon, 2007). The pathway involves inhibition of the anaphase promoting complex (APC). APC inhibition further results in high levels of securin and cyclin B, which in turn, sustain cohesion between sister kinetochores.
Among the most well studied SAC components are Mad1, Mad2, Mad3/BubR1, Bub1, Bub3 and Mps1 (Musacchio and Salmon, 2007). In metazoans, proteins such as Cenp-E, and components of RZZ complex: ZW10 (Zeste-White 10), Rod (Rough deal) and Zwint have been identified to play a role in SAC signaling (Karess et al., 2005, Musacchio and Salmon, 2007). Components of the SAC signaling pathway differ in mode of action and display different sensitivity to the attachment and tension (Musacchio and Salmon, 2007). Rod, for example, was shown to respond to the attachment state by pole-ward transfer from kinetochores along kinetochore microtubules (Basto et al., 2004, Karess et al., 2005). This behaviour has been described as shedding or streaming and is dependent on dynein/dynactin complex (Howell et al., 2001).
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