NHEJ1
Description
The NHEJ1 (non-homologous end joining factor 1) is a protein-coding gene located on chromosome 2.
Non-homologous end-joining factor 1 (NHEJ1), also known as Cernunnos or XRCC4-like factor (XLF), is a protein that in humans is encoded by the NHEJ1 gene. XLF was originally discovered as the protein mutated in five patients with growth retardation, microcephaly, and immunodeficiency. The protein is required for the non-homologous end joining (NHEJ) pathway of DNA repair. Patients with XLF mutations also have immunodeficiency due to a defect in V(D)J recombination, which uses NHEJ to generate diversity in the antibody repertoire of the immune system. XLF interacts with DNA ligase IV and XRCC4 and is thought to be involved in the end-bridging or ligation steps of NHEJ. The yeast (Saccharomyces cerevisiae) homolog of XLF is Nej1.
== Phenotypes == In contrast to the profound immunodeficiency phenotype of XLF deletion in humans, deletion of XLF alone has a mild phenotype in mice. However, combining a deletion of XLF with deletion of the ATM kinase causes a synthetic defect in NHEJ, suggesting partial redundancy in the function of these two proteins in mice.
== Structure == XLF is structurally similar to XRCC4, existing as a constitutive dimer with an N-terminal globular head domain, an alpha-helical stalk, and an unstructured C-terminal region (CTR).
== Interactions == XLF has been shown to interact with XRCC4, and with Ku protein, and it can also interact weakly with DNA. Co-crystal structures of XLF and XRCC4 suggest that the two proteins can form hetero-oligomers via head-to-head interaction of alternating XLF and XRCC4 subunits. These XRCC4-XLF filaments have been proposed to bridge DNA prior to end ligation during NHEJ. Formation of XRCC4-XLF oligomers can be disrupted by interaction of the C-terminal domain of XRCC4 with the BRCT domain of DNA ligase IV.
== Hematopoietic stem cell aging == Deficiency of NHEJ1 in mice leads to premature aging of hematopoietic stem cells as indicated by several lines of evidence including evidence that long-term repopulation is defective and worsens over time.
NHEJ1 is a DNA repair protein involved in non-homologous end joining (NHEJ), essential for fixing double-strand breaks (DSBs) and V(D)J recombination. It plays a vital role in NHEJ by facilitating the ligation of mismatched and non-cohesive DNA ends. In collaboration with PAXX, it assists DNA polymerase lambda (POLL) in joining non-cohesive DNA ends. NHEJ1 can also cooperate with XRCC5-XRCC6 (Ku) to stimulate XRCC4-mediated joining of blunt and mismatched DNA ends. Research suggests NHEJ1 may form filaments with XRCC4 to bridge DNA, holding broken DNA together during repair. Alternatively, a single NHEJ1 dimer may interact with XRCC4 to ensure precise DNA end alignment. NHEJ1 binds DNA in a length-dependent manner. It primarily exists as a homodimer when not associated with XRCC4. NHEJ1 interacts with XRCC4 through a head-to-head interaction, forming a key component of the core long-range NHEJ complex, alongside PRKDC, LIG4, XRCC4, XRCC6/Ku70, XRCC5/Ku86. PAXX is an additional component of the NHEJ complex. After autophosphorylation, PRKDC detaches from DNA, forming the short-range NHEJ complex, which includes LIG4, XRCC4, XRCC6/Ku70, XRCC5/Ku86, and NHEJ1/XLF. NHEJ1 interacts with POLL, promoting its recruitment to DSBs and stimulating its end-filling activity.
NHEJ1 is also known as XLF.
