NHEJ1 Human

NHEJ1 was initially discovered as the protein mutated in five patients who exhibited growth retardation, microcephaly, and immunodeficiency . The protein is indispensable for the NHEJ pathway, which is one of the primary mechanisms for repairing DSBs in DNA. Unlike homologous recombination, which requires a homologous template for repair, NHEJ directly ligates the broken DNA ends without the need for a homologous sequence .

Patients with mutations in the NHEJ1 gene also suffer from immunodeficiency due to defects in V(D)J recombination, a process that generates diversity in the antibody repertoire of the immune system . This highlights the critical role of NHEJ1 in both DNA repair and immune system function.

Structurally, NHEJ1 is similar to XRCC4 and exists as a constitutive dimer. It comprises an N-terminal globular head domain, an alpha-helical stalk, and an unstructured C-terminal region . NHEJ1 interacts with DNA ligase IV and XRCC4, and is thought to be involved in the end-bridging or ligation steps of the NHEJ process .

In humans, deletion of NHEJ1 results in severe immunodeficiency. However, in mice, the deletion of NHEJ1 alone has a mild phenotype. Interestingly, combining the deletion of NHEJ1 with the deletion of the ATM kinase causes a synthetic defect in NHEJ, suggesting partial redundancy in the function of these two proteins in mice .

NHEJ is a critical pathway for repairing DSBs, which can occur due to various factors such as ionizing radiation, oxidative stress, and certain chemicals . Failure to repair these breaks can lead to genetic instability, developmental delays, and increased susceptibility to cancer . NHEJ1, as a key player in this pathway, is therefore vital for maintaining genomic integrity and preventing disease.