Functional genetics reveals a role for the proteasome in regulating centromere assembly

Centromeres play a crucial role in linking chromosomes to spindle microtubules during mitosis. This is primarily achieved through two key proteins, CENP-A and CENP-T. CENP-T acts as a powerful scaffold for kinetochore assembly, and concentrating it at improper locations can lead to the formation of kinetochore-like structures. However, the mechanism by which cells prevent excess CENP-T from acting at non-centromere sites is not well understood.

Utilizing optical pooled screening, researchers have now uncovered the role of the proteasome in regulating CENP-T levels and controlling its localization.

The study reveals that CENP-A deposition machinery is essential for proper centromere formation. Interestingly, non-centromere CENP-T is degraded in a ubiquitin- and proteasome-dependent manner. In contrast, CENP-T that is incorporated into centromeres remains stable. Unbound CENP-T at non-centromere sites is rapidly turned over, with the CENP-T histone fold region being sufficient to confer sensitivity to the proteasome.

Quiescent cells, which disassemble their centromeres, continue to express CENP-T but eliminate it through continuous degradation.

In summary, while CENP-A is primarily controlled through regulated deposition, cells additionally regulate CENP-T by selectively degrading the unincorporated protein. This dual control mechanism ensures that CENP-T functions correctly at centromere sites and is prevented from acting aberrantly at non-centromere locations.