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. 1979 Oct;40(4):513–522. doi: 10.1038/bjc.1979.216

A new theory of carcinogenesis*

R Holliday
PMCID: PMC2010067  PMID: 497103

Abstract

Although many carcinogens are mutagens, there is no direct evidence that the cancer-cell phenotype is the result of gene mutation. Transplantation experiments have strongly indicated that malignant cells can arise or revert to the normal phenotype in the absence of mutation. It is suggested that damage to DNA followed by repair triggers the epigenetic changes in gene expression which are responsible for malignancy. We previously proposed that methylation of specific DNA sequences adjacent to structural genes determines whether or not transcription will occur. Specific methylases are required for the switching on of genes and for the stable maintenance of the methylated state, which provides a basis for the control of gene expression in differentiated cells. It is now seen that damage to DNA followed by repair, just before or just after DNA replication, can lead to the loss of methyl groups. This can induce a switch in gene activity which is heritable, but potentially reversible. The known large difference in the probability of malignant transformation in cells of rodents and large mammals is hard to explain if mutation is responsible. On the other hand, this new theory provides an explanation for this difference, since the probability of epigenetic changes in gene activity will depend on the activity of methylating enzymes and the rate of excision repair. The theory is supported by the evidence that excision repair is more efficient in cultured fibroblasts from large long-lived animals than from small short-lived ones.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

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