160 KARL G. LARK 



contrast to the micronuclcus which maintains tiie genetic continuity of 

 the cell) starts simultaneously at the ends of the two lobes and proceeds 

 toward the center. Similarly, in paramecia, synthesis of DNA is initiated 

 simultaneously in the macro- and micronuclei, although synthesis is 

 completed in the latter within a much shorter time than the former 

 (Woodard et al., 1961). This suggests that the initiation and rate of 

 DNA synthesis in both the macro- and micronuclcus may be controlled 

 by a similar mechanism. (However, see Section V,A below.) 



The above examples, though only a few of the large number to be 

 found in the literature, illustrate the type of control in which we are 

 interested. 



B. THE LEVEL OF BIOCHEMICAL CONTROL 



From our present biochemical knowledge, what possibilities exist 

 which could serve as a basis for a control mechanism? 



Figure 5 is a diagrammatic representation of the sequence of bio- 

 chemical steps in the synthesis of DNA. The experimental basis for 

 this sequence has been discussed extensively in the first chapter of this 

 book. Mechanisms for controlling the biosynthesis of DNA may, in 

 theory, be encountered at several levels. 



The requirement for deoxynucleotide triphosphates as the substrate 

 for polymerization makes the production of these precursors an im- 

 portant point of control in the synthesis of DNA (Bessman et al., 

 1958). (Control, at a level less specific than this, would simultaneously 

 affect other synthetic processes such as RNA and protein synthesis. For 

 this reason only more specific control mechanisms will be considered.) 

 The synthesis of these molecules, in turn, may be controlled at: 



(a) the conversion of ribonucleotides to dcoxyribonucleotides (Rei- 

 chard et al., 1961) and the formation of thymidylic acid (Fried- 

 kin, 1959), and/or 



(6) the phosphorylation of deoxy ribonucleotides to the trij)hosphate 

 form (Lehman et al., 1958). 



Thus, the rates at which tlie triphosphates are formed are governed by 

 several enzyme reactions subject to control through feedback inhibition 

 or repression (Pardee, 1961). Alternatively, competitive factors may be 

 operative; for example, a precursor substrate such as a ribonucleotide 

 may have been depleted by the synthesis of compounds other than 

 DNA. 



The actual polymerization of DNA presents a variety of opportuni- 

 ties for the operation of a control mechanism. This reaction requires the 

 participation of the "old" or pre-existent DNA which acts as both a 



