What Is the Ku70/80 Complex and What Does It Do?

The Ku70/80 complex is a set of proteins that acts as a first responder to severe DNA damage. It is a heterodimer composed of two different but related protein subunits, known as Ku70 and Ku80. These proteins work together to preserve the integrity of the genetic code within our cells. Their function is a core aspect of cellular maintenance, initiating a cascade of events to mend breaks in the DNA structure.

Defining the Ku70/80 Complex

The name “Ku” originates from the Japanese patient in whom the complex was first identified as an autoantigen in an autoimmune disease. The numbers 70 and 80 correspond to the approximate molecular weights of the two protein subunits, Ku70 and Ku80, in kilodaltons. In humans, these proteins are encoded by the XRCC6 and XRCC5 genes, respectively. The two subunits are structurally similar and join together to form a functional unit.

This combined structure forms a distinctive ring or basket shape that is perfectly suited for its function. The ring-like architecture allows the complex to encircle and thread onto the end of a DNA molecule. This unique method of binding enables it to slide along the DNA. This interaction is not dependent on the specific sequence of the DNA bases but rather on the physical structure of the broken end.

The Core Role in DNA Repair

A double-strand break (DSB), where both strands of the DNA double helix are severed, is a severe form of genetic damage. These breaks can lead to the loss of genetic information or chromosomal rearrangements if not repaired. The primary pathway cells use to fix these breaks is called Non-Homologous End Joining (NHEJ), a process initiated by the Ku70/80 complex.

Ku70/80’s first job in the NHEJ pathway is detection. It acts as the cell’s initial sensor, quickly identifying and binding to the exposed, broken termini of the DNA. The abundance of Ku70/80 molecules in a cell nucleus ensures that this response is rapid, securing the site of damage.

After binding, the complex performs a protective function. By encircling the broken ends, Ku70/80 shields them from cellular enzymes called nucleases, which would otherwise degrade the exposed DNA. This protection prevents the loss of genetic code from the ends of the break. The complex also holds the two ends of a broken DNA molecule together, stabilizing them for repair.

Finally, Ku70/80 acts as a recruitment platform. It serves as a molecular scaffold, attracting other repair proteins to the damage site. It directly recruits the DNA-dependent protein kinase catalytic subunit (DNA-PKcs), forming the active DNA-PK complex. This larger assembly then brings in final components, including the XRCC4-DNA Ligase IV complex, to ligate the two broken ends back together.

Function in Telomere Maintenance

Beyond mending broken DNA, the Ku70/80 complex has a separate function in maintaining the structural integrity of chromosomes. At the end of every chromosome are protective caps called telomeres. These repeating sequences of DNA prevent the natural ends of chromosomes from being mistaken for damage and protect them from degradation.

A cell must distinguish the natural ends of telomeres from the hazardous ends of a double-strand break. Ku70/80 binds to the telomeres, effectively hiding them from the cell’s own DNA repair machinery. Without the Ku complex guarding these ends, the cell could misidentify a telomere as a DSB and incorrectly initiate the NHEJ pathway.

Such a mistake can lead to the fusion of one chromosome end to another. This type of chromosomal instability can be a precursor to cell death or cancerous transformation. Therefore, Ku70/80’s presence at telomeres serves as a “do not repair” signal, preserving the normal architecture of the genome.

Connection to Disease and Aging

When the Ku70/80 system malfunctions, it can have significant health consequences, particularly for the immune system. The process of V(D)J recombination, which creates diverse antibodies and T-cell receptors, intentionally creates and then repairs double-strand breaks. Ku70/80 is required for this process, and defects can lead to Severe Combined Immunodeficiency (SCID).

Failures in the Ku70/80 complex are also linked to cancer. When DSBs are not repaired correctly, it can lead to mutations and chromosomal rearrangements. This genomic instability is a hallmark of cancer, and deficiencies in Ku function can predispose an individual to developing various malignancies.

Ku70/80 function is also connected to the aging process. The accumulation of unrepaired DNA damage contributes to cellular senescence, a state where cells stop dividing, and to the overall aging phenotype. Studies in mice have shown that a deficiency in Ku70 leads to features of premature aging, suggesting that a decline in DNA repair efficiency contributes to aging.