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__Abstract__ Proper maintenance of the genome is crucial for survival of all organisms. It is of major importance for reproduction and development, that the information encoded in the genome is replicated correctly. However, endogenous and exogenous DNA-damaging agents are constantly threatening the integrity of the genome. When a cell detects damage, it can arrest the cell cycle at specific checkpoints (G1/S, G2/M and intra-S). The activation of cell cycle checkpoints provides time to repair DNA lesions before they can be converted into permanent mutations. Incorrect repair or accumulation of DNA damage results in genome instability, which may lead to impaired functioning of the cell and even to the development of cancer. Therefore, all organisms have a complex network of DNA repair mechanisms, each of which is able to repair a subset of lesions. The biological significance of DNA repair mechanisms is underlined by the large number of repair genes, many of which are conserved from yeast to humans. The importance of the DNA repair pathways is also emphasized by the fact that defects in DNA repair genes often lead to cancer predisposition in humans. When DNA damage cannot be repaired properly, the cell can either go into apoptosis or can co

V(D)J recombination of Ig and TCR loci is a stepwise process during which site-specific DNA double-strand breaks (DSBs) are made by RAG1/RAG2, followed by DSB repair by nonhomologous end joining. Defects in V(D)J recombination result in SCID characterized by absence of mature B and T cells. A subset of T -B-NK+ SCID patients is sensitive to ionizing radiation, and the majority of these patients have mutations in Artemis. We present a patient with a new type of radiosensitive T-B -NK+ SCID with a defect in DNA ligase IV (LIG4). To date, LIG4 mutations have only been described in a radiosensitive leukemia patient and in 4 patients with a designated LIG4 syndrome, which is associated with chromosomal instability, pancytopenia, and developmental and growth delay. The patient described here shows that a LIG4 mutation can also cause T -B-NK+ SCID without developmental defects. The LIG4-deficient SCID patient had an incomplete but severe block in precursor B cell differentiation, resulting in extremely low levels of blood B cells. The residual DH-JH junctions showed extensive nucleotide deletions, apparently caused by prolonged exonuclease activity during the delayed DH-JH ligation process. In conclusion, different LIG4 mutations can result in either a developmental defect with minor immunological abnormalities or a SCID picture with normal development.

V(D)J recombination of Ig and TCR loci is a stepwise process during which site-specific DNA double-strand breaks (DSBs) are made by RAG1/RAG2, followed by DSB repair by nonhomologous end joining. Defects in V(D)J recombination result in SCID characterized by absence of mature B and T cells. A subset of T-B-NK+ SCID patients is sensitive to ionizing radiation, and the majority of these patients have mutations in Artemis. We present a patient with a new type of radiosensitive T-B-NK+ SCID with a defect in DNA ligase IV (LIG4). To date, LIG4 mutations have only been described in a radiosensitive leukemia patient and in 4 patients with a designated LIG4 syndrome, which is associated with chromosomal instability, pancytopenia, and developmental and growth delay. The patient described here shows that a LIG4 mutation can also cause T-B-NK+ SCID without developmental defects. The LIG4-deficient SCID patient had an incomplete but severe block in precursor B cell differentiation, resulting in extremely low levels of blood B cells. The residual D(H)-J(H) junctions showed extensive nucleotide deletions, apparently caused by prolonged exonuclease activity during the delayed D(H)-J(H) ligation process. In conclusion, different LIG4 mutations can result in either a developmental defect with minor immunological abnormalities or a SCID picture with normal development.