NHEJ1 Gene

The NHEJ1 gene (NHEJ1 stands for Non-Homologous End Joining Factor 1) is a protein-coding gene located on chromosome 2q35. The NHEJ1 gene encodes a DNA repair factor essential for the nonhomologous end-joining pathway, which preferentially mediates the repair of double-strand breaks. Mutations in this gene cause several types of severe combined immunodeficiencies.

The encoded DNA repair protein, is involved in non-homologous end joining of DNA (NHEJ) (Pastwa E et al. 2003). It is required for double-strand break (DSB) repair and V(D)J recombination and plays a key role in NHEJ by promoting the ligation of different non-matching and non-contiguous ends (see below. NHEJ mechanisms for repair of double-strand break DSBs). Here, the protein works in concert with PAXX as well as DNA polymerase lambda (POLL) to promote the linkage of non-cohesive DNA ends. The DNA repair protein acts together with XRCC5-XRCC6 (Ku) to enable XRCC4-mediated linkage of DNA ends and different . It thereby associates with XRCC4 to form alternating helical filaments that can bridge DNA. The XRCC4-NHEJ1/XLF subcomplex binds to DNA fragments of a DSB in a highly diffusive manner and robustly bridges two independent DNA molecules, keeping fragmented DNA in close proximity to each other. The mobility of the bridges ensures that the ends remain accessible for further processing by other repair factors.

Diseases associated with NHEJ1 include:

• Severe combined immunodeficiency with microcephaly, growth retardation and sensitivity to ionizing radiation (OMIM: 611291).
• and
• Chromosome 2Q35 duplication syndrome (syndactyly type I; OMIM: 185900).

Note: Double-strand breaks in DNA result from genotoxic stresses (e.g., irradiation) and are among the most damaging DNA lesions.

1. Ahnesorg P et al. (2006) XLF interacts with the XRCC4-DNA ligase IV complex to promote DNA nonhomologous end-joining. Cell 124: 301-313.
2. Buck D et al. (2006) Cernunnos, a novel nonhomologous end-joining factor, is mutated in human immunodeficiency with microcephaly. Cell 124: 287-299.
3. Callebaut I et al. (2006) Cernunnos interacts with the XRCC4-DNA-ligase IV complex and is homologous to the yeast nonhomologous end-joining factor Nej1. J Biol Chem 281: 13857-13860.
4. Dai Y et al. (2003) Nonhomologous end joining and V(D)J recombination require an additional factor. Proc. Nat. Acad. Sci. 100: 2462-2467.
5. Pastwa E et al (2003) Non-homologous DNA end joining. Acta biochimica Polonica 50:891-908.
6. Zhong Q et al (2002) Deficient nonhomologous end-joining activity in cell-free extracts from Brca1-null fibroblasts. Cancer research 62:3966-3970