LKB1

LIG4

LIG4 (DNA Ligase IV) is an essential enzyme in the process of DNA repair, specifically involved in the non-homologous end joining (NHEJ) pathway. This enzyme plays a critical role in the repair of double-strand breaks (DSBs) in DNA, which can occur due to various factors such as ionizing radiation, oxidative stress, and during the process of V(D)J recombination in the immune system.

Structure and Function

LIG4 is a member of the DNA ligase family, which is responsible for joining DNA strands by catalyzing the formation of phosphodiester bonds. The enzyme is composed of several domains that facilitate its function:

• DNA Binding Domain: This domain allows LIG4 to recognize and bind to the DNA ends that need to be joined.
• Adenylation Domain: This domain is responsible for the activation of the enzyme through the formation of a ligase-adenylate intermediate.
• OB-fold Domain: This domain is involved in protein-protein interactions, particularly with other components of the NHEJ machinery.

LIG4 functions in conjunction with other proteins such as XRCC4, XLF, and DNA-PKcs to efficiently repair DSBs. The enzyme is recruited to the site of damage where it ligates the broken DNA ends, restoring the integrity of the genome.

Role in V(D)J Recombination

LIG4 is crucial for the process of V(D)J recombination, which is essential for the development of the immune system. During this process, the enzyme helps to join the coding ends of immunoglobulin and T-cell receptor genes, allowing for the generation of diverse antigen receptor repertoires.

Clinical Significance

Mutations in the LIG4 gene can lead to a rare disorder known as LIG4 syndrome, characterized by immunodeficiency, microcephaly, and increased sensitivity to ionizing radiation. This condition highlights the importance of LIG4 in maintaining genomic stability and proper immune function.

Research and Therapeutic Implications

Understanding the function and regulation of LIG4 is critical for developing therapeutic strategies for diseases associated with DNA repair deficiencies. Inhibitors of LIG4 are being explored as potential treatments for cancer, as they can enhance the efficacy of radiotherapy and chemotherapy by preventing the repair of therapy-induced DNA damage.

Also see

• DNA Repair
• Non-Homologous End Joining
• V(D)J Recombination
• XRCC4
• DNA Ligase