Ku80

Ku80 is a protein that plays a critical role in the repair of DNA double-strand breaks (DSBs), a type of DNA damage that can lead to cell death or cancer if not properly repaired. Ku80, along with its partner protein Ku70, forms the Ku heterodimer, which is essential for the non-homologous end joining (NHEJ) pathway of DNA repair. This pathway is one of the primary mechanisms by which cells repair double-strand breaks in DNA.

Function

The primary function of Ku80 is to bind to the ends of double-strand breaks in DNA. Once bound, Ku80 and Ku70 help to protect the DNA ends from degradation and facilitate the recruitment of other proteins necessary for the repair process. The Ku heterodimer acts as a scaffold for the assembly of the NHEJ machinery, which includes proteins such as DNA-PKcs (DNA-dependent protein kinase, catalytic subunit), XRCC4 (X-ray repair cross-complementing protein 4), and Ligase IV, among others. These proteins work together to trim the broken DNA ends, fill in missing nucleotides, and ligate the ends back together, thereby restoring the integrity of the DNA molecule.

Structure

Ku80 is characterized by a unique three-dimensional structure that allows it to bind tightly to DNA. It consists of a von Willebrand factor A (vWA) domain at its N-terminus, which is involved in the interaction with DNA, and a larger C-terminal SAP (SAF-A/B, Acinus, and PIAS) domain that is thought to be involved in protein-protein interactions. The interaction between Ku70 and Ku80 is mediated by their respective C-terminal regions, forming a stable heterodimer that can efficiently bind to DNA.

Clinical Significance

Mutations in the gene encoding Ku80 can lead to defects in the NHEJ pathway, resulting in increased sensitivity to DNA-damaging agents and a predisposition to cancer. Additionally, Ku80 has been implicated in the aging process. Studies in model organisms have shown that mutations affecting Ku80 can lead to premature aging phenotypes, suggesting a role for DNA repair efficiency in the determination of lifespan.

Ku80 is also of interest in the field of cancer therapy. Given its essential role in DNA repair, targeting Ku80 or the NHEJ pathway more broadly is being explored as a strategy to sensitize cancer cells to radiation or chemotherapy, which induce DNA damage.

Research Directions

Research on Ku80 continues to explore its role in DNA repair, aging, and cancer. Efforts are underway to better understand the molecular details of its interaction with DNA and other proteins in the NHEJ pathway. Additionally, the development of inhibitors targeting Ku80 or the NHEJ pathway is an active area of research in the context of improving cancer treatment outcomes.

See Also

• DNA repair
• Non-homologous end joining
• Cancer therapy
• Aging