V. MOLECULAR MECHANISM OF MUTATIONS 



221 



may occur either when BU enters DNA, as a "mistake in incorporation" 

 (Fig. 6A), or after it has been incorporated into it, as a "mistake in 

 replication" (Fig. 6B). Hence, both kinds of base pair transitions, G-C 

 into A-T and vice versa, should be inducible with this agent. Although 

 BU-induced nuitations apparently are due to the Bl' incoi'poration, the 



B 



Fig. 6. The induction of base pair transitions by o-bromouracil. A. Mistake in 

 incorporation. During DNA duplication dBUTP rarely may pair "by mistake" with 

 a G present in DXA and the dBUMP is incorporated into the new DNA strand. This 

 initiates a base pair change since in the next DNA duplication dATP pairs with 

 this BU, A being the "normal" complementary base of BU, and dAMP is incorpo- 

 rated into the new strand. Thus eventually an A-T pair appears in some of the 

 progeny DNA in place of the original G-C pair. B. Mistake in replication. BU first 

 is incorporated into DNA by pairing with its normal complementar.y base A. This 

 increases the propensity of this base pair to mutate since BU undergoes pairing 

 mistakes more frequently than T. In one of the subsequent DNA duplications 

 dGTP may pair with BU and the incorporation of dGMP into the new DNA strand 

 leads to the eventual appearance of a G-C pair in place of the original A-T pair. 



above scheme shows that the frequency of forward mutations is not 

 necessarily proportional to the amount of BU incorporated (Litman and 

 Pardee, 1956) since the ratio of mistakes in incorporation to mistakes in 

 replication may vaiy. For the induction of reverse nuitations in bacteria 

 such a proportionality has been shown (Strelzoff, 1962i. 



The higher frecjuency of pairing mistakes which BU apparently 

 undergoes as compared to T is probably due to the higher electronega- 

 tivity of Br as compared to that of the methyl group in T. The pyrim- 

 idine ring gets poorer in electrons and apparently can lose the hydrogen 

 in the 3-position more easily than T, thus giving rise to the ionized 

 or tautomeric form of BU. This suggests the possibility that BU induces 



