Ataxia Telangiectasia: An Inherited Human Disease Involving Radiosensitivity, Malignancy and Defective DNA Repair

Summary

A unique feature of ataxia telangiectasia (AT), a hereditary multisystem disease, is extreme sensitivity to ionizing radiation, observed both clinically and in cell culture. Hence, we have measured the DNA repair capabilities of ten diploid fibroblast strains derived from unrelated AT donors, following anoxic ⁶⁰Co γ-irradiation. Compared to two control strains, six of the ten mutant strains are markedly deficient in γ-induced repair replication. Two defective strains were defined further. While capable of rejoining single-strand breaks normally, both are impaired in the initial incision step in excision repair of base defects, assayed as γ-modified sites sensitive to a Micrococcus luteus endonuclease activity. Cell fusion studies assign three repair-deficient strains to two complementation groups; this result, coupled with a normal repair-replication ability in four of the ten AT strains, indicates genetic heterogeneity in the disease. AT strains appear otherwise normal, including their ability to repair UV damage. Aside from providing molecular insight into this complex disorder, our findings characterize AT as a γ-ray analogue of the UV-sensitive skin disease, xeroderma pigmentosum. Moreover, since AT patients are cancer-prone, faulty DNA repair is implicated in neoplastic transformation. Finally, given that (i) impaired embryonic differentiation best explains the clinical features of AT and (ii) defective DNA repair is of etiological relevance, we are led to conclude that DNA damage can lead to congenital malformations; thus, enzymatic DNA repair processes play a vital role in normal neonatal development.