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

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. irradiation in 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 the recA mutation 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.

Disorders of B cells and helper T cells in the pathogenesis of the immunoglobulin deficiency of patients with ataxia telangiectasia.

“…There have been many attempts to show a DNA repair defect in AT biochemically. However, so far all tests for single or double stranded break repair have failed to show any convincing deficiency (36). In addition to observations concerning abnormal X-ray sensitivity, there have been studies indicating chromosomal abe.…”

Cancer predisposition, carcinogen hypersensitivity, and aberrant DNA metabolism

“….. property of' an A-T gene present in single dosage. In contradistinction to XP strains, A-T strains are not hypermutable by the agent to which they display hypercytotoxicity (Bridges, 1981;Bridges and Harnden, 1982). In fact, A-T cells may well be hypomutable by X radiation.…”

“…One attractive unifying hypothesis is that these mutant cells are defective in executing the recombinational exchanges considered essential for repair of radiogenic two-strand lesions, such as double-strand breaks or possibly DNA interstrand crosslinks (Bridges, 1981;Waldmann et al, 1983;Paterson et a1.,1984). We further speculate that the primary signals for triggering radiogenic inhibition of replicon initiation in normal cells are those chain openings introduced by recombination enzymes in the course of processing two-strand lesions, and that A-T cells are impaired in operating on some subclass of these radioproducts.…”

Genetic Effects on the Longevity of Cultured Human Fibroblasts. II

“…The results with CS establish a further relationship between premature ageing of individuals and short lifespan of their cells in culture. Al though these CS patients and their cells are extremely sensitive to UV light, they are not so far reported to be cancer-prone or to have chromosome abnormalities [2,18]. It is possi ble that the premature ageing of these fibro blasts is not related to any defect in repair, but rather to a more direct effect on the ageing process itself.…”