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DNA Repair (Amst). 2014 Apr;16:84-96. doi: 10.1016/j.dnarep.2014.02.011. Epub 2014 Mar 11.

The clinical impact of deficiency in DNA non-homologous end-joining.

Author information

1
Genome Damage and Stability Centre, Life Sciences, University of Sussex, Brighton BN1 9RQ, UK.
2
Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK.
3
Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK. Electronic address: p.a.jeggo@sussex.ac.uk.

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.

KEYWORDS:

(Severe) combined immunodeficiency – (S)CID; Double strand break repair; Human syndromes; Mammalian cells; V(D)J recombination

PMID:
24629483
DOI:
10.1016/j.dnarep.2014.02.011
[Indexed for MEDLINE]

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