The organization of genetic material relies on a family of proteins known as kleisins to manage and structure chromosomes. Kleisins partner with Structural Maintenance of Chromosomes (SMC) proteins to form molecular machines. These SMC-kleisin complexes are involved in the conformational transitions of DNA, ensuring genomic integrity.
Understanding Kleisin Structure and Core Function
Kleisin proteins are characterized by globular domains at both their N-terminus and C-terminus, separated by a flexible central region. This structure is conserved across different species, from bacteria to humans. The primary function of a kleisin is to act as a physical bridge.
The C-terminal domain of the kleisin binds to the “head” domain of one SMC protein, while the N-terminal domain associates with the “neck” region of a second. This interaction fastens the two SMC proteins together, converting them from an open V-shape into a closed, ring-like structure.
The resulting SMC-kleisin ring physically encircles one or more DNA strands in a mechanism known as topological entrapment. This process is regulated by ATP, which fuels changes in the SMC heads, allowing the ring to open and close to load or release DNA. The kleisin subunit itself acts as the clasp or gate of this molecular ring.
Kleisins Orchestrating Chromosome Segregation
A prominent example of a kleisin-driven process is chromosome segregation during cell division, managed by a complex called cohesin. The kleisin subunit in this complex is a protein known as Scc1. After DNA replication, cohesin acts as a molecular glue, holding the identical sister chromatids together.
The cohesin ring, with its Scc1 component, encircles the two sister chromatids to physically tether them. This linkage ensures that sister chromatids are correctly attached to the mitotic spindle, the machine that pulls chromosomes apart. Proper attachment is a prerequisite for their accurate distribution into two new daughter cells.
The separation of sister chromatids is a regulated event marking the transition into anaphase. This is triggered by the enzymatic cleavage of the Scc1 kleisin subunit by a specialized protease called separase. This action breaks open the cohesin ring, dissolving the link between the sister chromatids and allowing them to be pulled to opposite poles of the cell.
The controlled destruction of the kleisin subunit is an irreversible step. The precise timing of Scc1 cleavage prevents the premature separation of chromatids, which would lead to an unequal distribution of chromosomes.
Kleisins Driving Chromosome Architecture
Beyond holding chromosomes together, kleisins are central to organizing and compacting them. This function is carried out by SMC-kleisin complexes known as condensins. Eukaryotic cells have two types, Condensin I and Condensin II, which work together using kleisin subunits like CAP-H and CAP-H2.
Condensin’s primary role is to compact the immense length of chromosomal DNA. During mitosis, condensin complexes organize chromatin into the dense, tightly packed chromosomes characteristic of a dividing cell. This compaction prevents the long DNA strands from becoming tangled or damaged during segregation.
The mechanism for this is thought to involve DNA loop extrusion. The condensin ring binds to DNA and, using energy from ATP, actively pulls the DNA through its structure. This extrudes a growing loop and organizes the chromosome into a series of loops, shortening its overall length.
The two condensin types contribute to this process distinctly. Condensin II is involved early, establishing a scaffold of large chromatin loops. Condensin I then associates with chromosome arms to facilitate further compaction.
Consequences of Kleisin Malfunction
Malfunctions in kleisin proteins can lead to significant cellular consequences. Errors in cohesin’s Scc1 subunit can cause failures in sister chromatid segregation. This can result in aneuploidy, a condition where daughter cells inherit an incorrect number of chromosomes, which is a feature of many cancer cells.
Defects in genes coding for kleisins are linked to human developmental disorders known as cohesinopathies. For instance, Cornelia de Lange syndrome and Roberts syndrome are caused by mutations that impair cohesin’s function. These conditions are characterized by a wide range of developmental abnormalities.
Genomic instability from faulty kleisin function is also a contributor to cancer. Errors in chromosome segregation can lead to the loss of tumor-suppressing genes or the duplication of genes that promote uncontrolled cell growth. Dysregulation of both cohesin and condensin is frequently observed in tumors.
The impact of kleisins extends beyond segregation and condensation. Other SMC-kleisin complexes, like the SMC5/6 complex, use their kleisin components for DNA repair. By organizing chromatin, kleisin-containing complexes also play a part in regulating gene expression.