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Researchers used optical pooled screening to investigate how cells regulate two key centromere proteins, CENP-A and CENP-T, which are essential for chromosome segregation during cell division. They discovered that while CENP-A is controlled through regulated deposition, CENP-T is regulated through selective degradation by the proteasome: CENP-T incorporated at centromeres remains stable, but any excess CENP-T not bound to centromeres is rapidly degraded in a ubiquitin- and proteasome-dependent manner. This mechanism prevents CENP-T from inappropriately assembling kinetochore structures at non-centromere sites, which could otherwise disrupt chromosome segregation.
Why it matters
This work reveals a fundamental quality control mechanism that prevents chromosome segregation errors during cell division. Understanding how cells prevent mislocalization of kinetochore assembly factors could have implications for cancer research, as chromosome segregation defects are a hallmark of cancer cells and can drive tumor evolution.
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⚠️ Preprint – Noch nicht peer-reviewed
Dieser Artikel wurde noch nicht von unabhängigen Experten begutachtet. Die Ergebnisse sind vorläufig und sollten mit Vorsicht interpretiert werden.
Centromeres link chromosomes to spindle microtubules to direct their segregation during mitosis. The vertebrate centromere is built on two critical DNA-binding proteins, the histone H3-variant CENP-A and histone fold protein CENP-T. CENP-T is a potent scaffold for kinetochore assembly, such that concentrating it at ectopic sites is sufficient to build kinetochore-like structures. How cells prevent excess CENP-T from acting at non-centromere sites remains unclear. Here, using optical pooled screening to systematically define the requirements for CENP-A and CENP-T localization, we recover the established CENP-A deposition machinery and reveal a specific role for the proteasome in controlling CENP-T levels. We find that non-centromere CENP-T is degraded in a ubiquitin- and proteasome-dependent manner. Whereas centromere-incorporated CENP-T is stable, CENP-T that is not bound to centromeres is rapidly turned over, with the CENP-T histone fold region sufficient to confer proteasome sensitivity. Quiescent cells, which disassemble their centromeres, continue to express CENP-T but eliminate it through continuous degradation. Thus, whereas CENP-A is controlled primarily through regulated deposition, cells additionally control CENP-T by selectively degrading the unincorporated protein.
Source: Functional genetics reveals a role for the proteasome in regulating centromere assembly