Nuclear lamin A-associated proteins are required for centromere assembly

Area of Science:

• Cell Biology
• Molecular Biology
• Genetics

Background:

• Nuclear envelope (NE) reformation and mitotic exit involve the assembly of Lamin A-associated proteins (LAAPs) at chromosomal core domains.
• The precise identity and function of these chromosomal core domains, particularly their relationship with centromeres, remain unclear.

Approach:

• Investigated the spatial overlap between chromosomal core domains and centromeres/kinetochores during mitotic telophase.
• Examined the impact of inhibiting LMNA and core-localized LAAPs (BANF1, Emerin) on centromere assembly and NE reformation.
• Assessed the biochemical interactions between LAAPs and centromeric/kinetochore proteins.
• Analyzed the effects of LAAP inhibition on mitotic progression, chromosome segregation, and the localization of centromeric proteins (Mis18 complex, HJURP, CENP-A loading factors).

Key Points:

• A distinct section of the chromosomal core domain, termed the kinetochore proximal core (KPC), overlaps with centromeres/kinetochores.
• Inhibiting LMNA and LAAPs perturbs centromere assembly and NE reformation, indicating a functional link.
• LAAPs interact biochemically with centromere and inner kinetochore proteins, and their inhibition severely impairs mitosis and chromosome segregation.
• A mutual dependence exists between LAAP and centromere assembly at the core domains.
• LAAP inhibition disrupts the localization of key proteins (Mis18 complex, HJURP) essential for CENP-A loading.

Conclusions:

• LAAP assembly at the core domain is critical for centromere function and integrity.
• LAAPs play a vital role in the proper loading of new centromeric proteins, including CENP-A, during or immediately after mitotic exit.
• This study proposes a model where LAAPs are essential for establishing functional centromeres post-mitosis, ensuring accurate chromosome segregation.