What Is the Role of the Centromere During Cell Division?
Explore the centromere's role in cell division, from chromosome alignment to segregation, and understand its impact on genetic stability.
Cell division ensures genetic material is accurately passed from one generation of cells to the next. A key player in this process is the centromere, a specialized chromosomal region essential for proper chromosome movement and segregation. Without it, cells would struggle to distribute their DNA correctly, leading to significant consequences.
Centromere Structure And Organization
The centromere is a specialized chromosomal region that regulates chromosome behavior during cell division. Unlike other chromosomal regions, its structure is defined by epigenetic modifications and unique protein compositions rather than solely by DNA sequence. In most eukaryotes, the centromere contains a variant histone protein, CENP-A, which replaces conventional histone H3 in nucleosomes. This substitution provides centromeric chromatin with a distinct structural and functional identity necessary for chromosome dynamics.
Centromeres vary across species. In budding yeast (Saccharomyces cerevisiae), centromeres are defined by a specific DNA sequence spanning about 125 base pairs. In contrast, most multicellular eukaryotes, including humans, have regional centromeres extending over hundreds of kilobases to megabases of repetitive satellite DNA. These sequences do not encode proteins but help recruit centromere-specific proteins and establish a stable chromatin environment. The presence of CENP-A-enriched chromatin is a universal hallmark of centromere identity.
A network of associated proteins supports centromeric chromatin. CENP-A nucleosomes attract additional centromere-associated proteins, including the constitutive centromere-associated network (CCAN), which stabilizes centromeric chromatin across cell generations. CENP-A deposition occurs primarily during the G1 phase of the cell cycle, ensuring centromere identity is inherited. Disruptions in this process can lead to centromere instability, which is linked to chromosomal abnormalities and diseases such as cancer.
Kinetochore Formation And Microtubule Attachment
The kinetochore is a protein complex that assembles on the centromere and connects chromosomes to the spindle microtubules. Its formation ensures chromosomes are properly captured and aligned during mitosis. The CCAN provides a stable foundation for outer kinetochore components, which interact with spindle microtubules and drive chromosome movement.
Kinetochores must establish and maintain stable microtubule attachments while allowing for error correction. This occurs in two steps: initial lateral attachment followed by end-on conversion. In early mitosis, microtubules make transient lateral contacts with kinetochores before transitioning to end-on attachments that resist mechanical forces. The Ndc80 complex, a core outer kinetochore component, plays a central role in this transition by directly interacting with microtubule plus-ends. Microtubule-binding proteins such as the Ska complex further stabilize these attachments.
To prevent improper attachments, error correction mechanisms monitor kinetochore-microtubule interactions. Aurora B kinase phosphorylates kinetochore proteins when tension is absent, weakening incorrect attachments and allowing microtubules to detach and reattach correctly. When proper tension is established, Aurora B activity decreases, stabilizing the connection. This system is crucial for maintaining genomic integrity, as errors in kinetochore-microtubule attachment are a major source of aneuploidy.
Role In Chromosome Segregation
Accurate chromosome segregation ensures each daughter cell receives a complete and identical set of genetic material. The centromere, through its association with the kinetochore, serves as the primary site for spindle microtubule attachments. Once chromosomes align at the metaphase plate, tension from opposing spindle forces stabilizes these attachments, signaling that the cell is ready to proceed to anaphase.
During anaphase, the mitotic spindle pulls sister chromatids toward opposite poles. The centromere facilitates this movement through kinetochore-microtubule interactions, allowing coordinated microtubule depolymerization at both the kinetochore and spindle pole ends. This movement, often described as a “Pac-Man” mechanism, is powered by motor proteins such as dynein and kinesin. Precise control prevents lagging chromosomes, which are associated with chromosomal instability and aneuploid conditions like trisomy 21.
Consequences Of Centromere Malfunction
Centromere dysfunction can lead to chromosome missegregation and aneuploidy. Improper chromosomal attachment to the spindle apparatus increases the likelihood of nondisjunction, where chromosomes fail to separate correctly. This contributes to conditions such as Down syndrome, caused by trisomy 21. Aneuploidy is also a hallmark of many cancers, with centromere defects frequently linked to tumor progression and poor prognosis.
Centromere instability can trigger chromosomal rearrangements, including translocations and breakage. When centromere integrity is compromised, whole chromosomes or large fragments may be lost, leading to structural abnormalities that drive cancer development. Certain aggressive cancers, such as glioblastomas and high-grade ovarian carcinomas, exhibit extensive chromosomal instability associated with centromeric defects. Overexpression or mislocalization of CENP-A has been observed in several malignancies, promoting abnormal kinetochore assembly and spindle attachment errors.