Cell division is a fundamental process that underpins all life, enabling growth, repair, and reproduction. At its core, cell division involves the precise duplication and distribution of genetic material, packaged into chromosomes. To ensure that each new cell receives a complete and accurate set, a sophisticated mechanism holds duplicated chromosomes together. This mechanism, known as chromatid cohesion, relies on proteins called cohesins to physically link sister chromatids until their separation.
Understanding Chromatid Cohesion and Cohesin
Chromatid cohesion is the process that keeps sister chromatids paired after DNA replication, ensuring their proper alignment and segregation during cell division. Sister chromatids are identical copies of a chromosome, formed during the S phase of the cell cycle when DNA is replicated. Holding them together prevents premature separation and helps ensure each daughter cell receives a complete set of genetic information.
The molecular complex responsible for this connection is cohesin, a ring-shaped protein structure. Cohesin is composed of four main subunits: two structural maintenance of chromosomes (SMC) proteins, SMC1 and SMC3, a kleisin subunit, and a stromalin subunit. The SMC proteins form a V-shaped structure, and the kleisin subunit bridges their heads, closing the ring. This ring-like architecture encircles the DNA of sister chromatids, physically linking them. Cohesin is loaded onto chromosomes during the G1 phase and becomes competent to hold sister chromatids together during DNA replication in the S phase.
Cohesin Regulation in Mitosis
In mitotic cell division, cohesin maintains sister chromatid cohesion, which is important for accurate chromosome segregation into two genetically identical daughter cells. During prophase and prometaphase, cohesin holds sister chromatids together along their entire length, facilitating their proper attachment to spindle microtubules from opposite poles of the cell.
The complete separation of sister chromatids at the onset of anaphase requires cohesin removal. This is achieved through proteolytic cleavage by the enzyme separase. Separase specifically cleaves the kleisin subunit of the cohesin complex, such as RAD21. This cleavage breaks the cohesin ring, leading to the dissolution of cohesion along the entire length of the sister chromatids, allowing them to pull apart and move to opposite poles of the cell.
Cohesin Regulation in Meiosis
Cohesin regulation during meiosis, the specialized cell division that produces gametes, involves a two-step removal process. In meiosis I, homologous chromosomes separate, but sister chromatids remain attached. Cohesin is removed from the chromosome arms but is specifically protected at the centromeres.
This centromeric protection is mediated by a protein called Shugoshin. Shugoshin recruits a phosphatase, PP2A, to the centromeres, which counteracts phosphorylation of the meiotic cohesin subunit Rec8, making it resistant to cleavage by separase in that region. The removal of cohesin from the chromosome arms allows homologous chromosomes to separate in anaphase I, while the protected centromeric cohesin ensures that sister chromatids remain linked.
In meiosis II, which resembles mitosis, the remaining centromeric cohesin holds sister chromatids together until anaphase II. Separase becomes active again and cleaves the protected centromeric Rec8, allowing sister chromatids to separate and move to opposite poles. Meiosis also utilizes specific cohesin components; for example, the kleisin subunit Rec8 often replaces RAD21/SCC1 found in mitotic cohesin, contributing to the unique regulation required for meiotic divisions.
Why Differential Cohesin Regulation Matters
The distinct regulatory mechanisms of cohesin in mitosis and meiosis ensure the accurate transmission of genetic information and facilitate sexual reproduction. In mitosis, the complete and simultaneous removal of cohesin during anaphase ensures sister chromatids separate precisely, leading to two genetically identical daughter cells. This precision is important for growth, tissue repair, and the maintenance of an organism’s somatic cells.
In contrast, the two-step removal of cohesin in meiosis is important for producing genetically diverse gametes. During meiosis I, selective cohesin removal from chromosome arms, while maintaining it at centromeres, allows homologous chromosomes to segregate independently. This initial separation reduces the chromosome number by half. Subsequently, the delayed removal of centromeric cohesin in meiosis II ensures sister chromatids properly separate, resulting in haploid cells. This regulation generates gametes with unique combinations of parental genes, contributing to genetic diversity in sexually reproducing organisms.