FASEB 2001 Summer Research Conference on Biological Methylation

Presented at the FASEB 2001 Summer Research Conference, "Biological Methylation", Saxton's River, Vermont, July 21-26, 2001.

Title: Genomics and Proteomics 2001: Controlling some of the DNAs, RNAs, and proteins which blueprint health, disease, and life span, by controlling their methylation & demethylation.

Victor Herbert, M.D., J.D., M.A.C.P., F.R.S.M. (London), Mount Sinai-NYU Health System & Bronx V.A. Medical Center

Five decades ago, Borek et al (1954) noted that when bacteria auxotrophic for methionine are deprived of methionine, their resultant less methylated RNA is under ìrelaxed controlî, i.e. is synthesized more rapidly. In 1965, we speculated in print that the demethylating effect of vitamin B₁₂ or folate deficiency could produce such "relaxed controlî in humans. Ley et al.(1982) noted it is probable that folate and vitamin B12 and their antagonists are involved in the control of gene expression because hypomethylation of their DNA may "switch on" normal genes and methylation may switch them off. Reviewing all this in our paper "The Inhibition of Some Cancers and the Promotion of Others by Folic Acid, Vitamin B12, and Their Antagonists"(Herbert V. In: Nutritional Factors in the Induction and Maintenance of Malignancy [Butterworth CE Jr, Hutchinson ML, Eds.]. New York: Academic Press, 1983:273-287), we wrote, ìI should like to suggest the hypothesis that deficiency of folate or vitamin B12, or any other cause of failure to methylate DNA and/or RNA, can activate malignancy by hypomethylation of oncogenes, and that methylating oncogenes can inhibit malignancy by making them dormantÖ. It is not much of a leap to suggest that hypomethylation of the DNA and/or RNA of oncogenes would switch them on (i.e., activate them), and methylation would switch them off. Perhaps some of the second cancers that develop after successful antimetabolic chemotherapy are due to the same chemotherapy that directly destroys an active cancer, demethylating an oncogene of a dormant cancer.î As others will discuss at this meeting, we now know that the repression of transcription by DNA methylation can occur through transcriptional repressive protein complexes (to which one can make inactivating antibodies) such as Dnmts, HDACs, and MBDs. We also know that hypermethylation is a double-edged sword: it can suppress oncogenes and/or their product RNAs and/or proteins, and thereby suppress cancer; conversely, it can repress the tumor suppressor genes, RNAs, and proteins which suppress angiogenesis and metastasis, and the DNA repair genes in malignant cells, thereby enhancing cancer growth and spread. In 2001, learning that ~90% of the human genome is essentially identical to ~90% of the bacterial genome, we see more clearly the wisdom of the researchers who for the past century used plants and then bacteria to determine what was likely to be so in humans. Gregor Mendel lives on.

CV#837A. Herbert V. Genomics and Proteomics 2001: Controlling some of the DNAs, RNAs, and proteins which blueprint health, disease, and life span, by controlling their methylation & demethylation. Presented at FASEB 2001 Summer Research Conference, "Biological Methylation", Saxton's River, Vermont, July 21-26, 2001.