Structural Basis for Mis18 Complex Assembly: Insights into Centromere Maintenance

Kernkonzepte

The Mis18 complex plays a crucial role in centromere maintenance by facilitating CENP-A loading through structural interactions.

Zusammenfassung

The Mis18 complex, consisting of Mis18α, Mis18ý, and Mis18BP1, is essential for maintaining centromere identity by depositing CENP-A. Structural analysis reveals the assembly of the hetero-octameric Mis18 complex composed of 4 Mis18α, 2 Mis18ý, and 2 Mis18BP1 subunits. The interaction between the Yippee domains and C-terminal helices of Mis18 proteins is critical for complex formation. Mutations disrupting these interactions affect centromere localization and CENP-A loading. The study highlights the importance of specific structural elements in the assembly and function of the Mis18 complex.

Statistiken

The hetero-octameric Mis18 complex consists of 4 Mis18α, 2 Mis18ý, and 2 Mis18BP1 subunits.
Mutating residues I201A/L205A or L212A/L215A/L219A in Mis18α disrupts its interaction with Mis18ý.
Disrupting the interaction between Mis18α and Mis18BP120-130 abolishes centromere localization and new CENP-A deposition.

Zitate

"Mutating residues I201A/L205A or L212A/L215A/L219A in Mis18α perturbed its ability to interact with other subunits."
"Disrupting the interaction between key components abolished centromere localization."
"The study provides insights into the structural basis of centromere maintenance by the Mis18 complex."

Wichtige Erkenntnisse aus

Structural Basis for Mis18 Complex Assembly: Implications for Centromere Maintenance

by Thamkachy,R.... um www.biorxiv.org 11-08-2021

https://www.biorxiv.org/content/10.1101/2021.11.08.466737v2

Tiefere Fragen

How does disrupting specific interactions within the Mis18 complex impact other cellular processes beyond centromere maintenance

Disrupting specific interactions within the Mis18 complex can have far-reaching consequences beyond centromere maintenance. The Mis18 complex plays a crucial role in recruiting CENP-A to centromeres, which is essential for accurate chromosome segregation during cell division. If the interactions within the Mis18 complex are disrupted, it can lead to defects in kinetochore assembly and microtubule attachment, resulting in chromosomal instability and aneuploidy. This disruption may also impact other cellular processes that rely on proper centromere function, such as DNA replication timing and checkpoint signaling during mitosis.
Furthermore, since the Mis18 complex is involved in regulating CENP-A levels at centromeres through active loading mechanisms, disrupting its interactions could result in aberrant CENP-A deposition or depletion. This dysregulation of CENP-A levels can affect not only centromere identity but also overall genome stability and gene expression patterns.

What alternative mechanisms might compensate for disrupted interactions within the complex

When specific interactions within the Mis18 complex are disrupted, alternative compensatory mechanisms may come into play to maintain essential cellular functions related to centromere maintenance. One possible compensatory mechanism could involve upregulating other pathways or proteins involved in CENP-A loading or stabilizing kinetochore-microtubule attachments. For example, additional chaperones or remodelers may be recruited to assist with CENP-A deposition if the Mis18 complex is compromised.
Moreover, cells might activate feedback loops or signaling cascades to sense disruptions in the Mis18 complex assembly and trigger compensatory responses. These responses could involve changes in gene expression profiles related to centromere maintenance or alterations in cell cycle progression checkpoints to mitigate any potential damage caused by disrupted interactions within the Mis18 complex.

How can understanding protein assembly at centromeres contribute to advancements in cancer research

Understanding protein assembly at centromeres holds significant promise for advancements in cancer research due to the critical role of centromeres and kinetochores in ensuring faithful chromosome segregation – a process often dysregulated in cancer cells leading to genomic instability and tumor development.
By elucidating how proteins like those within the Mis18 complex contribute to maintaining proper chromosomal architecture and function during cell division, researchers can identify novel targets for therapeutic interventions aimed at correcting errors associated with abnormal chromosome segregation observed frequently in cancer cells. Targeting components of these complexes could potentially disrupt key processes required for cancer cell proliferation while sparing normal cells.
Additionally, insights into protein assembly at centromeres may uncover biomarkers indicative of chromosomal instability linked with certain types of cancers – providing diagnostic tools for early detection or prognostic indicators guiding treatment strategies tailored towards mitigating genomic abnormalities characteristic of malignant transformation.