The Curious Chemical Biology of Cytosine: Deamination, Methylation,and Oxidation as Modulators of Genomic Potential

Abstract

A multitude of functions have evolved around cytosine within DNA, endowing the base with physiological significance beyond simple information storage. This versatility arises from enzymes that chemically modify cytosine to expand the potential of the genome. Some modifications alter coding sequences, such as deamination of cytosine by AID/APOBEC enzymes to generate immunologic or virologic diversity. Other modifications are critical to epigenetic control, altering gene expression or cellular identity. Of these, cytosine methylation is well understood, in contrast to recently discovered modifications, such as oxidation by TET enzymes to 5-hydroxymethylcytosine. Further complexity results from cytosine demethylation, an enigmatic process that impacts cellular pluripotency. Recent insights help us to propose an integrated DNA demethylation model, accounting for contributions from cytosine oxidation, deamination and base excision repair. Taken together, this rich medley of alterations renders cytosine a genomic “wild card”, whose context-dependent functions make the base far more than a static letter in the code of life.

Mutational landscape, clonal evolution patterns, and role of RAS mutations in relapsed acute lymphoblastic leukemia

“…Moreover, and with the exception of one T-ALL tumor, which showed a marked increase in mutation load at relapse, the mutation load of these leukemias was only modestly increased at relapse. Mechanistically, mutation pattern analyses support that ALL mutations originate by spontaneous deaminations during tumor initiation and that this mutation mechanism is also characteristic at the time of relapse (39). A corollary of these findings is that chemical mutagenesis, characteristically associated with increased frequency of transversions (40), does not seem to represent a major driver of tumor initiation or relapse-associated mutations in ALL.…”

Refining the Genetic Alphabet: A Late-Period Selection Pressure?

“…2) (Levy and Miller, 1998). Yet cytosine is the one base that nature has selected to exploit, and its modifications can make up a substantial presence in DNA (Poole et al, 2001;Nabel et al, 2011). From the viewpoint of genetic fidelity, deamination reactions of C, mC, and HmC are the most problematic, but Native to all RNA, is also generated from C in mRNA as part of the eukarya RNA editing process Potent mutagenic lesion that arises from cytosine deamination and misincorporation by DNA polymerase; is a glycosylase substrate…”

Lesion processing by a repair enzyme is severely curtailed by residues needed to prevent aberrant activity on undamaged DNA

“…Such a compromise in G·T activity can account in part for the relatively weak G·T activity of TDG, a trait that could potentially contribute to the hypermutability of CpG sites in cancer and genetic disease. D NA base excision repair (BER) plays an established role in maintaining genomic integrity, and recent studies indicate that BER is also essential for active DNA demethylation, a key element of epigenetic gene regulation (1)(2)(3). A central player in both processes is thymine DNA glycosylase (TDG), which initiates BER by excising damaged or modified forms of 5-methylcytosine (mC) that arise at 5′-CpG-3′ sites.…”