Some DNA-repair-deficient human syndromes and their implications for human health

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Abstract
Several human syndromes are described with which have been associated a deficiency in the ability to repair damage to cellular DNA. This deficiency is generally manifested as a sensitivity to DNA-damaging agents such as u. v. light, ionizing radiation, or psoralen photosensiti­zation (PUVA). In xeroderma pigmentosum (XP) a high frequency of light-induced skin cancers is correlated with hypermutability of fibro­blasts following u. v. irradiationin vitro, providing telling support for the somatic mutation theory of cancer. Closer inspection, however, reveals that a pseudopromoting action of light or PUVA may be equally import­ant in skin carcinogenesis in both XP and normal individuals. It is suggested that impairment of cell-mediated immune response in the skin (possibly by DNA damage) may be responsible for this pseudopromoting action. That more than an enhanced frequency of somatic mutation is necessary for early skin neoplasms is illustrated by Cockayne syndrome (and possibly patient 11961), where XP-like changes in the skin are not observed despite an enhanced u. v. mutability of cultured fibroblasts. Xeroderma pigmentosum, ataxia-telangiectasia and Cockayne syn­drome all show progressive neurological disease, suggesting that common factors are involved in DNA repair and the normal development and function of the nervous system. Fibroblasts from certain Huntington’s disease patients also show some sensitivity to ionizing radiation but this cannot at present be attributed to a DNA-repair deficiency. Patients with ataxia-telangiectasia also show a severely depressed immune response, and a search for other individuals with impaired im­munity revealed patient 46BR, whose cells are sensitive to a wide range of DNA-damaging agents. It is suggested that common factors may be involved in DNA repair and the proper development and functioning of the immune system. One possibility is (by analogy with therecAmutation in bacteria) that common steps exist between some types of DNA repair and the somatic recombination events that are involved in the generation of immunoglobulin genes. Human DNA-repair-deficient mutants may not yet have proved their value in yielding an understanding of the molecular mechanisms of DNA repair, but they have shown that several unexpected aspects of human health may be linked to functional DNA-repair processes.