DNA double strand break repair defects, primary immunodeficiency disorders, and 'radiosensitivity'.
OBJECTIVE
It is important to assess 'radiosensitivity' in patients suspected of immunodeficiency because underlying DNA double strand break (DSB) repair defects have considerable impact on V(D)J recombination, class switching and lymphocyte maturation, leading to increased infections and cancer risk. In addition, the phenotype of 'radiosensitivity' may identify patients with increased toxicity to radiation and chemotherapeutic agents and could impact upon their preparation for stem cell transplantation. To date, the gold standard for evaluating 'radiosensitivity' has been the colony-survival assay (CSA), which reflects the efficiency of DNA repair of DSBs as it impacts upon replication and cell survival. Other methods measure other aspects of DNA repair; however, their limited specificity often leads to false negatives for predicting 'radiosensitivity', especially clinical radiosensitivity. Lastly, clinical awareness of an overarching syndrome of DSB repair disorders, XCIND, could help to raise diagnostic levels of suspicion and, thereby, identify additional patients with new forms of immunodeficiency, cancer susceptibility and radiosensitivity.


RESULTS
Within the past year, three new radiosensitivity disorders of DSB repair have been described, involving deficiencies of RNF168, RAD50, and DNA-PKcs. These are truly translational advances because they validate laboratory models and allow new patients to be identified.


CONCLUSIONS
Recognizing compromised genome stability is important but difficult. We review the evidence for correlations between DSB repair, abnormal colony formation, clinical radiosensitivity and other laboratory methods.
Nahas
Shareef A
SA
UCLA, Department of Pathology and Laboratory Medicine, USA.
Gatti
Richard A
RA
D017766:Acid Anhydride Hydrolases; D003114:Colony-Forming Units Assay; D053903:DNA Breaks, Double-Stranded; D045643:DNA Repair Enzymes / Q000235:genetics / Q000276:immunology; D049914:DNA Repair-Deficiency Disorders / Q000235:genetics* / Q000276:immunology; D051747:DNA-Activated Protein Kinase / Q000235:genetics / Q000276:immunology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000276:immunology; D020022:Genetic Predisposition to Disease; D006801:Humans; D009154:Mutation; D009369:Neoplasms / Q000235:genetics / Q000276:immunology; D009687:Nuclear Proteins / Q000235:genetics / Q000276:immunology; D011836:Radiation Tolerance / Q000235:genetics* / Q000276:immunology; D016511:Severe Combined Immunodeficiency / Q000235:genetics* / Q000276:immunology; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000276:immunology
D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; C535210:RNF168 protein, human; D044767:Ubiquitin-Protein Ligases; D051747:DNA-Activated Protein Kinase; C497263:PRKDC protein, human; D017766:Acid Anhydride Hydrolases; C112158:RAD50 protein, human; D045643:DNA Repair Enzymes