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Chapter V: The Lactose Repressor

Walter Gilbert, Benno Müller-Hill


The repressor for the lactose operon has been the paradigm for negative control. The Jacob and Monod (1961) hypothesis proposed that control genes would make repressors which would turn off other genes. Regulatory genes, as distinct from “structural” genes, were to make substances that could directly affect a rate-determining step in the synthesis of the functional products of other specific genes. This rate-determining step defines a target for the control: a specific point of interaction for the controlling substance. Such a target, named an “operator,” could be a specific point on a DNA molecule. The binding of a substance to the region of the DNA molecule that serves as an initiation point for the synthesis of messenger RNA clearly could block (or affect or enhance) the synthesis of that messenger. Alternatively, the target for control could be a region on a messenger RNA molecule. The binding of a control substance to such a messenger could easily be imagined to block the attachment of ribosomes and hence the synthesis of proteins. The term “bind” simply supplies a specific physical picture. As far as any genetic arguments are concerned, any biochemical process that leads to the same result would serve. The control substance could modify bases, achieving the same ends through a chemical alteration of structure. The isolation of several repressors (Gilbert and Müller-Hill, 1966; Ptashne, 1967a; Riggs and Bourgeois, 1968; Pirrotta and Ptashne, 1969) and the demonstration that the operator is a region on a DNA molecule to which they bind...

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