Uracil, the RNA base, has been replaced in DNA by thymine, (which has the same base-pairing with guanine). However the synthesis of dTTP (more usually written TTP) requires dUTP:

Synthesis of dTMP from UDP

To what extent is dUTP (mis)incorporated into DNA?

  • $\begingroup$ This question is an attempt to complete a set of questions on the base and sugar differences between DNA and RNA. I will answer it myself if no other answers are forthcoming. $\endgroup$ – David Apr 3 '17 at 16:19
  • $\begingroup$ I have provided and accepted my own answer to this question as it was posted as an attempt to complete a set of questions on the base and sugar differences between DNA and RNA. This should not stop anyone commenting on or criticising of the answer — I shall be happy to make improvements. $\endgroup$ – David Apr 9 '17 at 21:12

There follows an attempt to answer my own question, which I think is important to consider in the general context of postings on SE Biology concerning uracil and thymine in DNA and RNA synthesis.

  1. There seems to be little misincorporation because of the low concentrations of dUTP in cells.

  2. Any small amount of misincorporation can be handled by the DNA repair system that exists in cells.

I base statement 1 on the work of Grogan et al., published in Biochemistry 50, 618–627 (2011). They showed that in both mouse and human cell lines that the normal concentration of dUTP (and dUMP) was low. I assume that this must reflect cellular activities of dUTPase and thymidylate synthase being sufficiently high to remove dUTP and dUMP, respectively as they are formed. When thymidylate synthase activity was inhibited by anticancer drugs, these nucleotides built up, as expected.

In support of Statement 2 I refer to a separate earlier study in fission yeast by Seiple et al. in Nucleic Acids Research 34, 140–151 (2006). They used the drug, 5-fluorouracil, to inhibit thymidylate synthase and found that it caused misincorporation of uracil into DNA with concommitant cell damage. The role of the DNA repair system in mitigating this damage was shown using a mutant in the Ung1 gene, which encodes DNA glycosylase — here the cell toxicity was much higher.

Although there are some inconsistancies between the different systems used, and difficulties of interpretation. I think that they provide general support for the two postulates. It would be useful if it were possible to locate kinetic data on the relevant enzymes to test my assumptions regarding the reason for the low dUTP concentration.


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