Non-homologous end joining

A DNA repair mechanism

Non-homologous end joining (NHEJ) is a pathway that repairs double-strand breaks (DSBs) in DNA. It is one of the two major pathways for repairing DSBs, the other being homologous recombination. NHEJ is considered a more error-prone repair mechanism compared to homologous recombination because it does not require a homologous template and can result in the loss or gain of nucleotides at the site of repair.

Mechanism

NHEJ involves several key steps and proteins that facilitate the repair of DSBs:

Recognition and Binding

The process begins with the recognition of the DSB by the Ku protein complex, which consists of two subunits, Ku70 and Ku80. The Ku complex binds to the DNA ends and protects them from degradation.

Recruitment of DNA-PKcs

Once the Ku complex is bound to the DNA ends, it recruits the DNA-dependent protein kinase catalytic subunit (DNA-PKcs). Together, these form the DNA-PK holoenzyme, which is crucial for the subsequent steps of NHEJ.

End Processing

The DNA ends are often not directly ligatable and require processing. This can involve the removal of damaged nucleotides or the addition of nucleotides to create compatible ends. Enzymes such as Artemis and Polynucleotide kinase/phosphatase (PNKP) are involved in this process.

Ligation

The final step in NHEJ is the ligation of the DNA ends. This is carried out by the DNA ligase IV complex, which is associated with the cofactor XRCC4 and the protein XLF (also known as Cernunnos). This complex seals the DNA break, completing the repair process.

Biological Significance

NHEJ is crucial for maintaining genomic stability, especially in non-dividing cells where homologous recombination is not feasible. It is also essential for the development of the immune system, as it is involved in V(D)J recombination, a process that generates diversity in antibodies and T-cell receptors.

Clinical Implications

Defects in NHEJ can lead to increased sensitivity to ionizing radiation and predisposition to cancer. Mutations in genes encoding NHEJ proteins are associated with several human disorders, including Severe Combined Immunodeficiency (SCID) and LIG4 syndrome.

Also see

• Homologous recombination
• DNA repair
• V(D)J recombination
• Ku protein
• DNA ligase IV