the regulation of Mps1 activity and its spatio-temporal distribution

gaps in our understanding of these processes and propose future research avenues to address them.

1. It’s got to be perfect: faithful chromosome segregation by attachment error correction and the spindle assembly checkpoint

When a cell divides, the two resulting daughter cells each inherit an exact copy of its genetic content in order to maintain healthy cell function. Equal genome inheritance is driven by the mitotic spindle. Microtubules emanating from opposite poles of the spindle capture structures known as kinetochores on the two sister chromatids of chromosomes that were formed during the genome replication phase of the cell cycle. The sister chromatids separate only when every chromosome has achieved biorientation, a state in which one sister chromatid is attached to microtubules emanating from only one of the two poles while the other has attachments only to the other pole [1]. The result is the distribution of a complete copy of the genome towards opposite ends of the dividing cell, allowing fission to generate genetically identical daughters [2]. Compromised fidelity of chromosome segregation is implicated in a number of pathologies including cancer and in defects in embryonic development [3–6].

2. All about that kinase: some Mps1 basics

These findings are somewhat controversial, and it will be important to show that acute inhibition of Mps1 during interphase impairs these processes.

3. Get busy: the orchestration of error correction and spindle assembly checkpoint by Mps1

4. Start it up: molecular events leading to Mps1 activation

It seems likely therefore that at least some nuclear Mps1 activity is generated before kinetochores are assembled but it is unknown if that activity comes from an NPC-localized pool or, for example, from a diffusible nucleoplasmic pool of Mps1. Such insight will have to await activity biosensors and mechanistic information on how Mps1 localizes to the NPC.

5. Come together: how Mps1 binds kinetochores

6. Under control: regulators of the interaction of Mps1 with kinetochores

7. Let it go: a suggestion for a revised model of Mps1 release from kinetochores

8. Keep ‘em separated: blocking access of Mps1 to its kinetochore substrates

9. All together now: a temporal model for human MPS1 function in mitosis

10. What else is there: outstanding questions

Understanding its[*] role in the protection of genome stability is far from complete, however, and several key lacunas need to be filled.   [(*) the kinase Mps1]

Very little is known about how and where this pool of Mps1 becomes activated.

Several questions as to how this is achieved are as yet unanswered.

How does dimerization of Mps1 occur and how does it affect the activation dynamics of the kinase?

What are the steps leading to full activation of the kinase, and what are the roles of specific NTE and MR modifications?

How exactly are Aurora B and ARHGEF17 involved in these initial Mps1–kinetochore interactions (figure 2C,D)?

Have all contributing factors been identified?

Is there, however, a role for such non-kinetochore Mps1 activity in the maintenance of a mitotic arrest after a full initial kinetochore-dependent SAC response has been mounted?

Once Mps1 is displaced from kinetochores, how exactly does inactivation take place and what are the dynamics of it?

where this residual Mps1 is binding and how much reduction of Mps1 levels is sufficient to tip the balance in favour of the phosphatases and switch off SAC signalling. [?]

Are the incompletely de-phosphorylated HEC1 molecules the ones that retain MPS1 due to a lower affinity for microtubules?

Is there a gradual reduction in Mps1 levels that tracks ever increasing microtubule occupancy, or is there a more switch-like behaviour?

Does SAC strength correlate with Mps1 kinetochore levels?

how is removal of Mps1 from microtubule-bound kinetochores compatible with its role in error correction?

Can error correction be maintained by, for example, less Mps1 activity than needed for the SAC, or are relevant error-correction and SAC substrates affected differently by the same reductions in Mps1 activity?

Elucidating the finer points of Mps1 regulation in the coming years will provide crucial insights into how genomic stability is ensured.