The polC (= dnaE) temperature-sensitive DNA polymerase III mutation from Escherichia coli BT1026 has been transduced into E. coli WP2 (to give CM731) and WP2 uvr A (to give CM741). In excision-deficient CM741 UV-induced Trp+ mutations progressively lost their photoreversibility during post-irradiation incubation at 34 degrees. Immediately after transfer to 43 degrees, however, there was no further loss of reversibility although post-replication strand joining still occurred and uptake of 3H-thymidine into DNA continued for 20 to 30 min. In excision-proficient CM731, UV lesions capable of leading to Strr mutations disappeared during post-irradiation incubation at restrictive temperature and there was no increase in the number remaining after exposure to photoreversing light. In contrast, at permissive temperature, premutational lesions were not lost and became progressively converted into non-photoreverisble mutations. It is concluded that a function of the polC gene is necessary for error-prone repair to occur and that this function is defective at 43 degrees in the enzyme specified by the polC allele from BT1026. This function seems not to be essential for most post-replication or excision repair or for normal DNA replication and may be particularly involved in the insertion of incorrect bases during error-prone repair.

No abstract

No 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.

No abstract