Uracil and Thymidine

[LikeDaniel]

Hello,

Sorry to cross-post, but the nontrads told me I'd have a better chance of getting an answer here.

I'm studying for the MCAT and something has been bothering me not because I'm worried about encountering it on the MCAT, but because I don't fully understand it (and I'm curious).

I keep hearing that a common cause of mutations is uracil's similarity to thymidine. I understand that this is true, but I don't understand why it's true.

Wouldn't uracil be read the same way that thymidine would be? Or would it be skipped causing a frameshift mutation? Or would it "freak out" the reading protein and effectively act as a stop codon?

Willing to learn,
-LD

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[aldol16]

I keep hearing that a common cause of mutations is uracil's similarity to thymidine. I understand that this is true, but I don't understand why it's true.

Wouldn't uracil be read the same way that thymidine would be? Or would it be skipped causing a frameshift mutation? Or would it "freak out" the reading protein and effectively act as a stop codon?

I believe that one of the big problems isn't that uracil is similar to thymine but rather involves how you get the uracil mutation. Uracil mutations are usually caused by cytosines deaminating spontaneously to form uracil. If you look at their structures, these two bases are extremely similar (cytosine has an amine that can be converted to an imine easily and uracil has a ketone where that imine is). So if your cytosine mutates to uracil, that's a program because now it's going to pair with an A on the other strand instead of a G. That's a huge problem. Specifically, prokaryotic RNA polymerases will pair that uracil with an adenine on the other strand. But mammalian RNA polymerases have evolved a defense mechanism and will pair U in DNA with either A or G so it guards partially against this mutation.

In fact, this problem is so big that evolution has found a way around it. This is linked to why DNA has thymine instead of uracil. Thymine has an extra methyl "tag" that marks it as "I belong here in DNA." Uracil does not. So there are enzymes that go around checking the DNA after replication and if they come upon the uracil, they cut it out based on the absence of that methyl tag.

If you're interested, here are references:

http://www.nature.com/onc/journal/v21/n58/full/1205996a.html
https://www.ncbi.nlm.nih.gov/books/NBK22525/#_A3839_
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3659810/

 

[LikeDaniel]

Thank you for taking the time to reply (especially so thoroughly!). What you said makes a lot of sense.

I listened again to where I heard in ExamKrackers Audio Osmosis, and they definitely say thymine (in my sleepy stupor yesterday I said thymidine). I wonder if they simply made a mistake (which is what I'm leaning towards) or if there is also some kind of mutational risk between thymine and uracil, too.

Based on your input, I think it was probably just a slip of the tongue on their part since they were saying uracil and thymine together everywhere else in that "paragraph".

Thanks again for your help!

Sent from my SAMSUNG-SGH-I337 using SDN mobile

 

[aldol16]

I listened again to where I heard in ExamKrackers Audio Osmosis, and they definitely say thymine (in my sleepy stupor yesterday I said thymidine). I wonder if they simply made a mistake (which is what I'm leaning towards) or if there is also some kind of mutational risk between thymine and uracil, too.

It doesn't seem likely to me chemically that thymine would decompose into a uracil because that would require demethylation - the breaking of a strong C-C bond. However, it is quite possible that uracil might be substituted for thymine accidentally during replication. I'm not too familiar with that and so I don't have any insight into whether that happens to any great extent. I would assume that the proof-reading enzymes would fix that if it did, so T --> U wouldn't be very common.

 

[sazerac]

It doesn't seem likely to me chemically that thymine would decompose into a uracil because that would require demethylation - the breaking of a strong C-C bond. However, it is quite possible that uracil might be substituted for thymine accidentally during replication. I'm not too familiar with that and so I don't have any insight into whether that happens to any great extent. I would assume that the proof-reading enzymes would fix that if it did, so T --> U wouldn't be very common.

Wikipedia says uracil appears in DNA from both spontaneous cytosine deamination (resulting in GU pairs) and misincorporation of dUMP residues (resulting in AU pairs). It doesn't hint at which process occurs more frequently, but the first process sure shows up a lot more on biochemistry exams!

The enzyme Uracil-DNA glycosylase can fix both errors.

 

[aldol16]

Wikipedia says uracil appears in DNA from both spontaneous cytosine deamination (resulting in GU pairs) and misincorporation of dUMP residues (resulting in AU pairs). It doesn't hint at which process occurs more frequently, but the first process sure shows up a lot more on biochemistry exams!

Yeah, I would assume that the first occurs more frequently because if uracil is incorporated in place of thymine during DNA replication, then the proofreading enzymes can easily figure that out and take care of that. But the spontaneous degradation of cytosine is harder to control because it can occur after proofreading - especially since the process is fast, relatively speaking.