Mapping the kinetochore MAP functions required for stabilizing microtubule attachments to chromosomes during metaphase

Abstract

In mitosis, faithful chromosome segregation is orchestrated by the dynamic interactions between the spindle microtubules (MTs) emanating from the opposite poles and the kinetochores of the chromosomes. However, the precise mechanism that coordinates the coupling of the kinetochore components to dynamic MTs has been a long‐standing question. Microtubule‐associated proteins (MAPs) regulate MT nucleation and dynamics, MT‐mediated transport and MT cross‐linking in cells. During mitosis, MAPs play an essential role not only in determining spindle length, position, and orientation but also in facilitating robust kinetochore‐microtubule (kMT) attachments by linking the kinetochores to spindle MTs efficiently. The stability of MTs imparted by the MAPs is critical to ensure accurate chromosome segregation. This review primarily focuses on the specific function of nonmotor kinetochore MAPs, their recruitment to kinetochores and their MT‐binding properties. We also attempt to synthesize and strengthen our understanding of how these MAPs work in coordination with the kinetochore‐bound Ndc80 complex (the key component at the MT‐binding interface in metaphase and anaphase) to establish stable kMT attachments and control accurate chromosome segregation during mitosis.

The Ndc80 complex is essential for the initial kinetochore-microtubule capture during early mitosis

“…In addition to the established microtubule-binding sites within the Ndc80 complex, the internally located loop domain has also been reported to be important for the recruitment of Ndc80 accessory proteins such as the Ska complex and Cdt1 to human kinetochores, where they are required to form robust kMT attachments during metaphase (Amin et al, 2019; Monda and Cheeseman, 2018). We hence used the STLC treatment assay to test if the Hec1 loop domain was required for kMT capture.…”

“…On the other hand, the attachments in metaphase/anaphase are load-bearing (due to bi-attachment with microtubules of opposite spindle poles) and are stabilized with the help of protein factors that are accessory to Ndc80 (including the Ska1 complex, Cdt1, Astrin, etc. ), to prevent kinetochore detachment during chromosome segregation (Amin et al, 2019; Cheeseman and Desai, 2008).…”

The ciliopathy protein CCDC66 controls mitotic progression and cytokinesis by promoting microtubule nucleation and organization

“…Thereby, MAPs play essential roles during numerous cell cycle processes including MT nucleation, formation and organization of the mitotic spindle and central spindle, chromosome capture, alignment and segregation, cleavage furrow formation and abscission (Glotzer, 2009; Petry, 2016; Petry and Vale, 2015). Proteomic profiling of MT-based structures of dividing cells, functional screens and loss-of-function studies have identified hundreds of MAPs as regulators of mitosis and cytokinesis (Amin et al, 2019; Petry, 2016). However, key questions remain about their functions, mechanisms and links to disease as well as how they cooperate with different cellular structures (i.e.…”

Two XMAP215/TOG Microtubule Polymerases, Alp14 and Dis1, Play Non-Exchangeable, Distinct Roles in Microtubule Organisation in Fission Yeast

“…For instance, Alp14 and Dis1 form a complex with different MAP partners in a cell; Alp14 binds Alp7/TACC (Transforming Acidic Coiled-Coil), while Dis1 interacts with Mal3/EB1 [16,19]. In addition, during mitosis, the cellular localisation of Alp14 and Dis1 is different; Alp14 is first recruited to the spindle pole body (SPB, the fungal equivalent of the centrosome), while Dis1 is localised to the kinetochore [15,20,21,22,23].…”