Timed Chemical Tags Help Cells Divide Accurately

Jim Crocker
17th June, 2025

Timed Chemical Tags Help Cells Divide Accurately

Overexpression of the demethylase Jhd2 impairs kinetochore integrity, causing increased kinetochore declustering (a) and high rates of chromosome missegregation (b–d) that are directly linked to its catalytic activity reducing the methylation of the kinetochore protein Dam1 (e, f).

Image adapted from: Mishra et al. / CC BY (Source)

Key Findings

  • In budding yeast, a key protein's modification (Dam1 methylation) is precisely controlled during cell division, peaking when chromosomes align for proper distribution
  • The study surprisingly found that Jhd2, an enzyme, removes these methyl groups from Dam1, acting as a crucial regulator of this cell division process
  • Disrupting this balance by increasing Jhd2 leads to reduced Dam1 methylation, causing kinetochore problems and widespread chromosome errors, a hallmark of cancer
All living organisms rely on the precise and orderly division of their cells for growth, repair, and reproduction. A fundamental part of this process is the accurate distribution of chromosomes – the structures containing our genetic material – to each new daughter cell. This intricate dance is orchestrated by a complex cellular machine called the kinetochore. The kinetochore is a large protein assembly that forms on a specific region of each chromosome, known as the centromere[2]. Its crucial role is to act as the attachment point for spindle microtubules, which are like cellular ropes that pull the chromosomes apart during cell division, ensuring each new cell receives a complete and correct set[3]. Errors in chromosome segregation can have severe consequences. When chromosomes are not distributed evenly, cells end up with an abnormal number or structure of chromosomes, a condition known as chromosomal instability (CIN)[4]. CIN is a hallmark of many cancers, found in over 90% of solid tumors and blood cancers[4]. While CIN can be harmful to normal cells, paradoxically, it can also give cancer cells an advantage by increasing their diversity, making them more adaptable and resistant to treatments[4]. Understanding the mechanisms that prevent such errors is therefore critical for both basic biology and for developing new strategies against diseases like cancer. Recent research, conducted by scientists at the National Cancer Institute, NIH, The Catholic University of America, Queen Mary University of London, Frederick National Laboratory for Cancer Research, University of North Carolina, and Oregon State University[1], has shed new light on how the kinetochore's function is precisely regulated. The study focused on budding yeast, a widely used model organism for studying fundamental cellular processes due to its well-understood genetics and cellular machinery[3]. Specifically, the researchers investigated a vital component of the yeast kinetochore called the Dam1/DASH complex. Previous work had shown that a chemical modification, called methylation, on a specific part of the Dam1 protein (lysine residue 233) by an enzyme named Set1 is essential for the yeast's normal growth. If this methylation was prevented, the cells could not survive. The new study revealed that this Dam1 methylation is not just important, but is tightly controlled throughout the cell cycle, the series of events that a cell goes through as it grows and divides. The highest levels of Dam1 methylation were observed when cells were in metaphase, the stage of cell division where chromosomes align perfectly before being pulled apart. This suggests a critical role for this modification precisely when the kinetochore is under the most strain, making its load-bearing attachments to microtubules[3]. The researchers also found that the Set1 enzyme, responsible for adding the methyl group, directly interacts with Dam1 during metaphase, confirming its role in this cell cycle-dependent regulation. Even more surprisingly, the study uncovered an unexpected player in this regulatory process: Jhd2. Jhd2 is an enzyme previously known primarily for its role in removing methyl groups from histone proteins, which are involved in packaging DNA. However, the new research demonstrated that Jhd2 also interacts with and removes methyl groups from subunits of the Dam1 complex. This was a novel finding, as Jhd2 had not been previously linked to non-histone proteins like Dam1. To understand the impact of Jhd2's activity on Dam1, the scientists engineered yeast cells to produce excessive amounts of Jhd2. They observed that these cells had significantly reduced levels of methylated Dam1. This reduction in Dam1 methylation led to a cascade of problems: the cells showed growth defects, particularly in strains with existing kinetochore mutations, indicating a compromised kinetochore function. Furthermore, the researchers found reduced amounts of other crucial kinetochore proteins at the centromere[2] – the specific chromosomal region where the kinetochore assembles. Most critically, these cells exhibited defects in kinetochore "biorientation" (the proper attachment of sister kinetochores to microtubules from opposite poles of the cell) and, consequently, experienced widespread chromosome missegregation. This directly links the precise regulation of Dam1 methylation to the accurate distribution of chromosomes during cell division. In essence, this research identifies a crucial, cell cycle-dependent regulatory switch for the kinetochore through the methylation and demethylation of the Dam1 protein. The kinetochore acts as a "regulatory hub"[3], ensuring that the cell cycle progresses only when chromosomes are properly attached to the spindle. This study adds a new layer to our understanding of how this hub functions, showing that the precise timing of Dam1 methylation is vital for building and maintaining a functional kinetochore. Disruptions in this delicate balance, as shown by Jhd2 overexpression, lead to chromosome missegregation, a direct cause of chromosomal instability[4]. By unraveling these fundamental mechanisms of chromosome segregation, this study contributes significantly to our understanding of how cells maintain genetic stability and how errors can arise, potentially paving the way for future insights into diseases like cancer.

GeneticsBiochem

References

Main Study

1) Cell cycle dependent methylation of Dam1 contributes to kinetochore integrity and faithful chromosome segregation

Published 16th June, 2025

https://doi.org/10.1371/journal.pgen.1011760

Related Studies

2) Centromere Structure and Function.

https://doi.org/10.1007/978-3-319-58592-5_21

3) The composition, functions, and regulation of the budding yeast kinetochore.

https://doi.org/10.1534/genetics.112.145276

4) The two sides of chromosomal instability: drivers and brakes in cancer.

https://doi.org/10.1038/s41392-024-01767-7


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