Spindly attachments

Abstract

The attachment of chromosomes to spindle microtubules during mitosis is a delicate and intricate process on which eukaryotic cells critically depend to maintain their ploidy. In this issue of Genes & Development, Gassmann and colleagues (pp. 2385-2399 present an analysis of the recently discovered Spindly/SPDL-1 protein that casts new lights onto the attachment process and the way it relates to the control of cell cycle progression.

Figure 1.

Complexity of the dynamic kinetochore–microtubule interface. (A) The sister kinetochores of a bioriented sister chromatid pair at metaphase are connected to opposite spindle poles through one or more microtubules (the number of microtubules varies in different species). The closeup shows the configuration of end-on attachment with KMN networks bound to microtubules. (B) At anaphase, the sister chromatids have lost cohesion and are transported to opposite spindle poles. (C) Complexity of the kinetochore–microtubule attachment process. Black arrows indicate an action, such as “recruitment” or “microtubule binding.” Dotted black arrows indicate that an uncertainty exists on the actual species performing the action. Green arrows define positive regulation. Red lines with a smaller perpendicular line at one end indicate negative regulation. We did not distinguish whether the negative or positive regulation is exercised on an action or the species that carries out the action. The KMN network mediates several actions, including kinetochore recruitment of the RZZ complex and of the SAC proteins Mps1, Bub1, BubR1, and Bub3, and the formation of stable end-on microtubule attachments. Most and probably all of the actions ascribed to the KMN network are positively regulated by the Aurora B kinase. Aurora B also suppresses improper kinetochore–microtubule attachments. The checkpoint proteins (in blue) positively regulate the process of end-on attachment. In the case of Mps1, this may occur through a positive regulation of Aurora B activity. In the case of Bub1 and BubR1, the target of regulation by these kinases is unknown. After recruitment to prometaphase kinetochores, the RZZ complex suppresses the ability of the KMN network to bind to microtubules. Once at kinetochore, the RZZ complex recruits Spindly, dynein, Mad1, and Mad2. Dynein mediates lateral attachment to microtubules, which in turn favors end-on attachment. The establishment of end-on attachment suppresses the kinetochore accumulation of the RZZ and of the other proteins whose kinetochore localization depends on the RZZ, as it instates the mechanism of “stripping.” See the text for details and references supporting this scheme.