Cell division is a fundamental biological process that allows organisms to grow, repair tissues, and reproduce. During this process, a cell divides into two or more daughter cells, and each new cell must receive a complete and accurate set of genetic information. This genetic material is organized into structures called chromosomes. Precise distribution of these chromosomes is crucial, as errors can have serious consequences. Accurate chromosome separation is essential for maintaining genetic stability.
The Foundation: Sister Chromatids and Cohesion
Genetic information is packaged into chromosomes, which replicate before cell division. After DNA replication, each chromosome consists of two identical copies, known as sister chromatids. These sister chromatids are physically linked along their length, sharing a common constricted region called the centromere.
This physical connection between sister chromatids, called sister chromatid cohesion, is mediated by the cohesin protein complex. Cohesin forms a ring-like structure, composed of subunits including SMC1, SMC3, SCC1 (Rad21), and SCC3 (SA1 or SA2). This ring encircles the sister chromatids, holding them together and ensuring their proper behavior during cell division.
The Dynamics of Cohesion: When It Forms and When It Breaks
Sister chromatid cohesion is established during the S phase of the cell cycle, when DNA replication occurs. This process is tightly coupled with DNA replication, ensuring cohesion forms as sister chromatids are generated. The cohesin complex is loaded onto chromosomes by specific proteins, such as Scc2 and Scc4. For cohesin to function, its SMC3 subunit must be chemically modified through acetylation by enzymes like Eco1 (Esco1/Esco2 in humans). This modification allows proteins like Sororin to stabilize cohesin on chromosomes, counteracting proteins that promote its removal.
Once established, cohesion is maintained throughout the G2 phase, prophase, and metaphase of cell division. Its eventual release marks the onset of anaphase, allowing sister chromatids to separate. This separation is triggered by separase, a protease enzyme. Separase cleaves a specific cohesin subunit, typically SCC1 (Rad21) in mitosis, opening the cohesin ring and dissolving the physical linkage. In vertebrates, much cohesin along chromosome arms is removed during prophase by a cleavage-independent mechanism, with only centromeric cohesin requiring separase for removal at anaphase.
The Unique Case: Cohesion’s Maintenance in Meiosis I
Meiosis is a specialized cell division producing reproductive cells, such as sperm and egg cells, each with half the parent cell’s chromosome number. This reduction occurs over two distinct divisions. In meiosis I, homologous chromosomes, one inherited from each parent, separate, but sister chromatids within each homologous chromosome remain attached. This selective maintenance of sister chromatid cohesion is essential for accurate chromosome segregation.
Cohesin along the arms of homologous chromosomes, containing a meiosis-specific subunit called Rec8, is cleaved by separase during anaphase I, allowing homologous chromosomes to disjoin. However, cohesin at the centromeres of sister chromatids is protected from this cleavage. This protection is attributed to Shugoshin proteins (Sgo1/Sgo2), which localize to centromeric regions. Shugoshin recruits protein phosphatase 2A (PP2A) to the centromeres. PP2A then dephosphorylates the Rec8 subunit of cohesin, preventing its cleavage by separase. This ensures sister chromatids remain linked at their centromeres throughout meiosis I, preparing them for separation in meiosis II.
The Impact of Cohesion Errors
Precise regulation of sister chromatid cohesion is essential for genomic stability. Errors in its establishment, maintenance, or timely release can lead to severe cellular consequences. If cohesion is not properly controlled, chromosomes may not segregate correctly, resulting in daughter cells with an abnormal number of chromosomes, a condition known as aneuploidy.
Aneuploidy is a significant cause of developmental disorders, such as Down syndrome, and is frequently observed in cancer cells. For instance, in human oocytes, weakening or loss of sister chromatid cohesion with increasing maternal age is a primary factor contributing to age-related aneuploidy and associated infertility. Thus, the intricate mechanisms governing sister chromatid cohesion are crucial for ensuring proper genetic material distribution and maintaining cellular and organismal health.