Cytosine, deamination

Mismatch Repair. Mispairs that break the normal base-pairing rules can arise spontaneously due to DNA biosynthetic errors, events associated with genetic recombination and the deamination of methylated cytosine (Modrich, 1987). With the latter, when cytosine deaminates to uracil, an endonuclease enzyme, /V-uracil-DNA glycosylase (Lindahl, 1979), excises the uracil residue before it can pair with adenine at the next replication. However, 5-methyl cytosine deaminates to form thymine and will not be excised by a glycosylase. As a result, thymine exits on one strand paired with guanine on the sister strand, that is, a mismatch. This will result in a spontaneous point mutation if left unrepaired. For this reason, methylated cytosines form spontaneous mutation hot-spots (Miller, 1985). The cell is able to repair mismatches by being able to distinguish between the DNA strand that exists before replication and a newly synthesized strand. 

Cytosine deamination (G ) Spontaneous/ chemicals Uracil glycosylase AP endonuclease DNA polymerase DNA ligase... 

Uracil DNA glycosylases, for example, found in most cells, specifically remove from DNA the uracil that results from spontaneous deamination of cytosine. Mutant cells that lack this enzyme have a high rate of G=C to A=T mutations. This glycosylase does not remove uracil residues from RNA or thymine residues from DNA. The capacity to distinguish thymine from uracil, the product of cytosine deamination—necessary for the selective repair of the latter—may be one reason why DNA evolved to contain thymine instead of uracil (p. 293). 

Base deamination is accelerated by nitrous acid and sodium bisulfite. Nitrous acid nonspecifically promotes base deamination in both double-stranded and single-stranded DNA. In contrast, sodium bisulfite specifically promotes cytosine deamination in single-stranded DNA. Some single-stranded regions do exist in cellular DNA, at least temporarily—for example, during transcription. In some cases, sodium bisulfite is used as a food additive. It is also used in the wine industry. 

Figure 22.26. Mechanistic model of somatic hypermutation. Somatic hypermutation is initiated by AID via cytosine deamination in single-strand regions of DNA. Uracil-containing DNA leads to mutagenesis by three different mechanisms replication, translesion synthesis, and gap filling.

The literature documents various situations in which C deamination is enhanced. These situations include the presence of C in cyclobutane pyrimidine dimers (a form of DNA damage caused by exposure to UV radiation see later discussion) or in mis-pairings with other bases or with alkylated bases (1). Cytosine deamination is also promoted in the presence of nitrons acid, a reaction that although not considered in this review, has lent much to our understanding of possible chemical mechanisms of spontaneous deamination (1). 

Cytosine, deamination, 894 Cytosine DPsA methyltransferase, 898 Cytosolic FEPCK, 189-191... 

Scheme for repair of cytosine deamination. The same mechanism could remove a uracil that is accidentally incorporated. 

S., and Zhang-Akiyama, Q.M. (2009) Generation, biological consequences and repair mechanisms of cytosine deamination in DNA. J. Radiat. Res., 50, 19-26. 

Schematic drawing showing how cytosine deamination could cause a mutation. (A)...

Deamination reaction converting cytosine to uracil. (B) Cytosine deamination, if not corrected, will result in a mutation from G-C to A-T after subsequent rounds of DNA... 

Fryxell K.J. and Zuckerkandl E. (2000). Cytosine deamination plays a primary role in the evolution of mammalian isochores. Mol. Biol. Evol. 17 1371-1383. 

Purine nucleosides behave similarly to their pyrimidine counterparts, but their contribution to the overall degradation is insignificant [44]. For instance, adenine is converted to hypoxanthine in single-stranded DNA at only 2-3% of the rate of cytosine deamination [48]. 

C-5 cytosine can spontaneously deaminate just as cytosine can. When C-5 cytosine deaminates, it forms thymidine, not uracil. Therefore uracil N-glycosylase, a DNA repair enzyme, will not recognize this product of deamination as an inappropriate base and will not remove it from the DNA, causing a transition mutation. 

It is used to maximize the maintenance of the integrity of the information encoded by DNA. Cytosine can spontaneously deaminate to form uracil this damage is repaired by base excision repair. If uracil rather than thymine were used in DNA, then correctly positioned uracil would be indistinguishable from that arising from cytosine deamination. Use of thymine (methylated uracil) in DNA avoids this problem. 

Pham, P., Bransteitter, R., Petruska, J., and Goodman, M. F. (2003). Processive AID-catalyzed cytosine deamination on ssDNA simulates somatic hypermutation. Nature 423, 103-107. 

The term nucleotide is used generically for both RNA and DNA units. The absence of a 2 -OH group in DNA prevents alkali-mediated cleavage of the 3 -5 phosphodiester cleavage observed in RNA and thus makes DNA more resistant to hydrolysis. Both RNA and DNA contain two types of purines, adenine (A) and guanine (G), and two types of pyrimidine bases (Fig. 1C). The second key difference between RNA and DNA is that while cytosine (C) is present in both RNA and DNA, RNA normally contains uracil (U), while DNA contains 5-methyluracil, called thymine (T), as the other pyrimidine base. The difference in chemical structure is reflected in the intrinsic chemical stability of these nucleic acids. The purine N-glycosyl bond in DNA is more unstable than in RNA, and as a result, purines are released much more easily from DNA by acid catalysis. Furthermore, cytosine deamination to produce U also occurs at a finite rate in DNA. 

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