title: The clinical impact of deficiency in DNA non-homologous end-joining.
abstract: DNA non-homologous end-joining (NHEJ) is the major DNA double strand break (DSB) repair pathway in mammalian cells. Defects in NHEJ proteins confer marked radiosensitivity in cell lines and mice models, since radiation potently induces DSBs. The process of V(D)J recombination functions during the development of the immune response, and involves the introduction and rejoining of programmed DSBs to generate an array of diverse T and B cells. NHEJ rejoins these programmed DSBs. Consequently, NHEJ deficiency confers (severe) combined immunodeficiency - (S)CID - due to a failure to carry out V(D)J recombination efficiently. NHEJ also functions in class switch recombination, another step enhancing T and B cell diversity. Prompted by these findings, a search for radiosensitivity amongst (S)CID patients revealed a radiosensitive sub-class, defined as RS-SCID. Mutations in NHEJ genes, defining human syndromes deficient in DNA ligase IV (LIG4 Syndrome), XLF-Cernunnos, Artemis or DNA-PKcs, have been identified in such patients. Mutations in XRCC4 or Ku70,80 in patients have not been identified. RS-SCID patients frequently display additional characteristics including microcephaly, dysmorphic facial features and growth delay. Here, we overview the clinical spectrum of RS-SCID patients and discuss our current understanding of the underlying biology.
authors.affiliation: Genome Damage and Stability Centre, Life Sciences, University of Sussex, Brighton BN1 9RQ, UK.
authors.forename: Lisa
authors.initials: L
authors.lastname: Woodbine
authors.affiliation: Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Gennery
authors.affiliation: Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK. Electronic address: p.a.jeggo@sussex.ac.uk.
authors.forename: Penny A
authors.initials: PA
authors.lastname: Jeggo
mesh_terms: D000818:Animals; D053903:DNA Breaks, Double-Stranded; D059766:DNA End-Joining Repair; D045643:DNA Repair Enzymes / Q000235:genetics / Q000378:metabolism; D042822:Genomic Instability; D006801:Humans; D051379:Mice; D009154:Mutation; D016511:Severe Combined Immunodeficiency / Q000235:genetics* / Q000473:pathology*
chemical_list: D045643:DNA Repair Enzymes
keywords: (Severe) combined immunodeficiency – (S)CID; Double strand break repair; Human syndromes; Mammalian cells; V(D)J recombination