Non-homologous end joining

Non-homologous end joining (NHEJ) is a pathway that repairs double-strand breaks (DSBs) in DNA. DSBs are among the most harmful types of DNA damage, which can lead to chromosome instability and, if not properly repaired, can result in cell death, cancer, and other diseases. Unlike homologous recombination (HR), which requires a homologous sequence to guide the repair, NHEJ directly ligates the broken DNA ends together, making it a critical repair mechanism, especially in the G1 phase of the cell cycle when sister chromatids are not available as templates for HR.

Mechanism[edit | edit source]

NHEJ involves several key steps and proteins. Initially, the Ku70/Ku80 heterodimer binds to the DNA ends, protecting them from degradation and aligning them for repair. The DNA-PKcs (DNA-dependent protein kinase, catalytic subunit) then joins the complex, forming the DNA-PK holoenzyme, which activates the repair process. Next, processing of the DNA ends may be required to make them compatible for ligation; this can involve filling in missing nucleotides by DNA polymerases (such as Pol μ and Pol λ) and removing damaged or mismatched nucleotides by nucleases like Artemis. Finally, the DNA ligase IV enzyme, in a complex with XRCC4 and XLF (also known as Cernunnos), ligates the DNA ends, completing the repair.

Importance[edit | edit source]

NHEJ is crucial for maintaining genomic stability. It is the predominant DSB repair mechanism in mammalian cells and is especially important in non-dividing cells, where HR is less active. NHEJ's ability to repair DSBs without the need for a homologous template makes it versatile, but it also introduces the risk of errors, such as deletions or insertions at the repair site, potentially leading to mutations. Despite this, the pathway's role in enabling lymphocytes to rearrange their DNA to produce diverse antibody repertoires through V(D)J recombination highlights its importance in adaptive immunity.

Clinical Significance[edit | edit source]

Defects in NHEJ components can lead to severe immunodeficiency diseases, such as Severe Combined Immunodeficiency (SCID) due to Artemis or DNA ligase IV syndromes. Moreover, the pathway's role in repairing DSBs makes it a target for cancer therapies. Inhibiting NHEJ can increase the sensitivity of cancer cells to radiation and chemotherapeutic agents that induce DSBs, offering a potential therapeutic strategy. However, targeting such a critical repair pathway must be approached with caution to avoid adverse effects on normal cells.

Research Directions[edit | edit source]

Research continues to uncover the complex regulation of NHEJ and its interplay with other repair pathways like HR. Understanding the precise mechanisms of NHEJ and its regulation provides insights into the fundamental processes of cell biology and offers potential targets for therapeutic intervention in cancer and other diseases associated with DNA repair defects.