Defective excision repair of γ-ray-damaged DNA in human (ataxia telangiectasia) fibroblasts

Abstract

ATAXIA telangiectasia (AT) (Louis–Bar syndrome) is a rare human neurovascular disease displaying an autosomal recessive pattern of inheritance^1–3. Affected individuals, although clinically normal at birth, symptomatically develop cerebellar ataxia (loss of muscular coordination) and oculocutaneous telangiectasis (chronic dilation of the small blood vessels) in early childhood. The course of the disease follows a variable progression commonly leading to total neurological incapacitation before puberty. Accessory complications include lymphoreticular neoplasia^2,3, bronchiectasis^1,2, recurrent sinopulmonary infections^1,2, decreased levels of serum immunoglobulins IgA and IgE (refs 3 and 4), impaired cellular immunity^3,4, and widespread chromosomal instability⁵. AT patients, on receiving conventional radiotherapy for tumour treatment, tend to develop unusually severe complications often culminating in premature death^6–8. Pronounced radiosenitivity is also observed at the cellular level in laboratory studies; the number of radiation-induced chromosomal aberrations is enhanced in leukocytes obtained from AT donors⁹. Moreover, diploid fibroblasts cultured from affected individuals exhibit a reduced ability to form colonies following exposure to γ radiation¹⁰ and radiomimetic chemicals¹¹. Since the principal damage induced by both types of agents occurs in the DNA and seems to be acted on by the same enzymatic repair mechanisms^12,13, it would seem probable that the molecular basis for the clinical radiosensitivity of AT patients stems from a deficient DNA repair mechanism. We therefore measured the DNA repair properties of AT fibroblasts after exposure to γ radiation. Data presented below provide direct biochemical evidence that diploid strains from AT donors are indeed impaired in DNA repair; in particular, these cell lines possess an enzymatic defect in an excision-type repair process operating on γ-modified nitrogenous base residues.