Researchers at The University of Osaka have identified an additional pathway crucial for the specification of centromeres, the attachment sites on chromosomes essential for accurate cell division. This discovery reveals that the cell component CENP-C can assume the role of Mis18C in guiding the Holliday Junction Recognition Protein (HJURP) to deposit the DNA-packaging histone CENP-A, thereby offering a parallel mechanism that supports successful mitosis and meiosis.
Background on Centromeres
Genetic material, comprising billions of base pairs in humans, requires precise and equal division during cell replication. The centromere, located on each chromosome, functions as the attachment point for cellular machinery responsible for separating chromosomes during cell division. The exact mechanisms governing centromere formation and function have been a subject of ongoing research.
Discovery of Parallel Pathway
The study, published in The EMBO Journal, focused on how the DNA-packaging histone CENP-A associates with and specifies the centromere's location. This process is vital for maintaining chromosome structure and appropriate gene expression. Researchers specifically investigated the Holliday Junction Recognition Protein (HJURP), a chaperone protein known for guiding centromere-identifying cell components to their correct chromosomal sites.
Observations indicated that HJURP failed to localize at the centromere when the expression of both CENP-C and Mis18C cell components was eliminated through a double knockout process. While Mis18C was previously known to facilitate HJURP's recognition for CENP-A deposition onto centromeres, the research revealed that CENP-C can also fulfill this function, providing an alternative pathway. The study further identified specific residues within HJURP that enable its binding to CENP-C.
Experimental Validation and Observations
Further analyses conducted in DT40 chicken cells confirmed the significance of these interactions for centromere function during cell division. When the interaction between HJURP and CENP-C was disrupted, errors in mitosis occurred, leading to a deceleration in cell growth.
A combined scenario, involving both the lack of interaction between HJURP and CENP-C and the removal of Mis18C, prevented CENP-A from incorporating into chromatin. This inhibition subsequently hindered cellular machinery from identifying the centromere's correct location.
Implications for Centromere Mechanisms
This work indicates a greater diversity in the sequence-independent epigenetic mechanism of centromere specification than previously understood. According to lead author Tetsuya Hori and senior author Tatsuo Fukagawa, the identification of dual pathways for recruiting HJURP for CENP-A deposition provides a foundation for future research into centromere mechanisms and diseases associated with errors in cell division.