How Cells Regulate Centromere Function

Accurate cell division depends on the even distribution of about three billion base pairs of genetic material between two new human cells. Central to this process is the centromere, a region near the middle of each chromosome where cellular machinery attaches to ensure equal chromosome separation. While scientists have long understood that the centromere is vital for successful division, the detailed mechanisms controlling its activity have remained unclear.

A study reported in The EMBO Journal by scientists at the University of Osaka identifies an additional pathway that governs how the DNA-packaging histone CENP-A associates with the centromere. This process is crucial for maintaining correct chromosome structure and regulating gene expression.

The research centers on the Holliday Junction Recognition Protein (HJURP), a chaperone that delivers CENP-A to centromeres. The team discovered that HJURP failed to localize to the centromere when both CENP-C and Mis18C were removed through a double knockout. Senior author Tatsuo Fukagawa explained, “Although it was known that Mis18C recognizes the chaperone HJURP to enable CENP-A’s deposition onto centromeres, we found that CENP-C can actually occupy Mis18C’s role in this process, providing a parallel pathway that helps ensure successful and timely mitosis or meiosis.” They also pinpointed the specific residues within HJURP responsible for binding to CENP-C.

Analyses using DT40 chicken cells confirmed these findings. When HJURP and CENP-C could not interact, cell division slowed and errors in mitosis occurred. When Mis18C was also absent, CENP-A failed to incorporate into chromatin, leaving the cellular machinery unable to identify the centromere’s position. This result demonstrated that both interaction pathways are necessary for proper centromere function during cell division.

Lead author Tetsuya Hori noted, “Our work reveals that this sequence-independent epigenetic mechanism of centromere specification has greater diversity than previously thought. Given how biologically fundamental the processes of mitosis and meiosis are, our finding that the cell has independent pathways for flagging the location of each chromosome’s centromere is valuable.”

By uncovering dual pathways controlling how centromere-associated proteins function together, this research enhances understanding of the molecular systems that maintain chromosomal stability through mitosis and meiosis. The findings provide a foundation for future investigations into centromere function and conditions linked to failures in cell division.