NHEJ1
Domain
The coiled-coil region mediates homodimerization.
The Leu-lock (Leu-115) site inserts into a hydrophobic pocket in XRCC4.
The XLM motif (also called the KBM motif or KBMX motif) and the interior region of the C-terminal tail preceding the XLM motif are essential for DNA end joining (PubMed:33289484). The sequence of the C-terminal tail is not critical for its role in end joining but it must be sufficiently long to interact with XRCC4 and to stabilize the interaction of XRCC4 with LIG4 (By similarity). A single XLM motif and C-terminal tail is sufficient to promote end joining (By similarity).
Function
DNA repair protein involved in DNA non-homologous end joining (NHEJ); required for double-strand break (DSB) repair and V(D)J recombination (PubMed:16439204, PubMed:16439205, PubMed:17317666, PubMed:17470781, PubMed:17717001, PubMed:18158905, PubMed:18644470, PubMed:20558749, PubMed:26100018). Plays a key role in NHEJ by promoting the ligation of various mismatched and non-cohesive ends (PubMed:17470781, PubMed:17717001, PubMed:19056826). Together with PAXX, collaborates with DNA polymerase lambda (POLL) to promote joining of non-cohesive DNA ends (PubMed:25670504, PubMed:30250067). May act in concert with XRCC5-XRCC6 (Ku) to stimulate XRCC4-mediated joining of blunt ends and several types of mismatched ends that are non-complementary or partially complementary (PubMed:16439204, PubMed:16439205, PubMed:17317666, PubMed:17470781). In some studies, has been shown to associate with XRCC4 to form alternating helical filaments that bridge DNA and act like a bandage, holding together the broken DNA until it is repaired (PubMed:21768349, PubMed:21775435, PubMed:22228831, PubMed:22287571, PubMed:26100018, PubMed:27437582, PubMed:28500754). Alternatively, it has also been shown that rather than forming filaments, a single NHEJ1 dimer interacts through both head domains with XRCC4 to promote the close alignment of DNA ends (By similarity). The XRCC4-NHEJ1/XLF subcomplex binds to the DNA fragments of a DSB in a highly diffusive manner and robustly bridges two independent DNA molecules, holding the broken DNA fragments in close proximity to one other (PubMed:27437582, PubMed:28500754). The mobility of the bridges ensures that the ends remain accessible for further processing by other repair factors (PubMed:27437582). Binds DNA in a length-dependent manner (PubMed:17317666, PubMed:18158905).
Involvement in disease
Severe combined immunodeficiency due to NHEJ1 deficiency
NHEJ1-SCID
SCID refers to a genetically and clinically heterogeneous group of rare congenital disorders characterized by impairment of both humoral and cell-mediated immunity, leukopenia and low or absent antibody levels. Patients with SCID present in infancy with recurrent, persistent infections by opportunistic organisms. The common characteristic of all types of SCID is absence of T-cell-mediated cellular immunity due to a defect in T-cell development. NHEJ1-SCID is characterized by a profound T- and B-lymphocytopenia associated with increased cellular sensitivity to ionizing radiation, microcephaly and growth retardation. Some patients may manifest SCID with sensitivity to ionizing radiation without microcephaly and mild growth retardation, probably due to hypomorphic NHEJ1 mutations.
None
The disease is caused by variants affecting the gene represented in this entry.
A chromosomal aberration involving NHEJ1 is found in a patient with polymicrogyria. Translocation t(2;7)(q35;p22).
Post-translational modifications
Phosphorylated by PRKDC at the C-terminus in response to DNA damage (PubMed:18644470, PubMed:22228831, PubMed:28500754). Phosphorylations by PRKDC at the C-terminus of XRCC4 and NHEJ1/XLF are highly redundant and regulate ability of the XRCC4-NHEJ1/XLF subcomplex to bridge DNA (PubMed:22228831, PubMed:28500754). Phosphorylation does not prevent interaction with XRCC4 but disrupts ability to bridge DNA and promotes detachment from DNA (PubMed:22228831, PubMed:28500754).
Sequence Similarities
Belongs to the XRCC4-XLF family. XLF subfamily.
Tissue Specificity
Ubiquitously expressed.
Cellular localization
- Nucleus
- Chromosome
- Localizes to site of double-strand breaks; recruitment is dependent on XRCC5-XRCC6 (Ku) heterodimer.
Alternative names
XLF, NHEJ1, Non-homologous end-joining factor 1, Protein cernunnos, XRCC4-like factor