I have been puzzled for many years about the lack of mutagenesis in nDNA in yeast cells grown in conditions of thymidylate deprivation or treated with drugs like methotrexate or 5-FdUMP. These conditions are intensely nDNA damaging and both clastogenic and recombinagenic. These growth conditions also increase mutation rates in mtDNA by orders of magnitude. In contrast, excess thymidylate is intensely mutagenic for both nDNA and mtDNA.
A potential explanation is that DNA-Uracil plays a role in MMR strand recognition.
This might contain the answer:
Article Non-canonical uracil processing in DNA gives rise to double-...
Yes it is. This can be seen clearly during antibody diversification when a lot of uracils arise from deamination of cytosine by activation-induced cytidine deaminase (AID). This occurs in both somatic hypermutation and class-switch recombination (as alluded to by Geoff).
Here's a good review of somatic hypermutation and talks about mismatch repair and its recognition of U:G mispairs.
https://www.annualreviews.org/doi/full/10.1146/annurev.biochem.76.061705.090740?url_ver=Z39.88-2003&rfr_id=ori%3Arid%3Acrossref.org&rfr_dat=cr_pub%3Dpubmed
These G:U mispairs can be replicated or progress through base excision repair or mismatch repair.
Also, here is a paper that biochemically describes the DNA substrates for the main mismatch repair enzymes in mammals (MSH2/6).
http://www.jbc.org/content/267/33/23876.long
Thank you very much both of you. It is difficult keeping up with the literature these days. It's the information age and I am very sorry that I only recently saw this beautiful piece of work.
My interest however is with A:U basepairing during semi-conservative nDNA and mtDNA replication not deamination of DNA-cytosine. Mitochondria do not have MMR so we can ignore them for now probably only mass action effects
In the nucleus however normal cells and normal dUTP/dTTP intracellular pools would insert 1 U per 1000 T,s approximately. Excess dTTP maybe inserting only 1/10,000 U per T. DNA-Ura( A:U pairing not deamination of C to generate G:U in situ) would thus inhibit MMR strand recognition and be intensely mutagenic. It is. UTP pools >>>dTTP from drugs like methotrexate or 5-FU would not be mutagenic at all. It isn't.
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