5carboxylcytosine

5-carboxylcytosine, abbreviated 5caC, is a pyrimidine nucleobase that is a carboxylated derivative of cytosine, featuring a carboxyl group at the fifth position of the ring. It is one of the oxidized forms of 5-methylcytosine (5mC) produced in DNA by the TET family of dioxygenases.

In the context of active DNA demethylation, 5caC is formed from 5mC through successive oxidation steps that also yield 5-hydroxymethylcytosine (5hmC) and 5-formylcytosine (5fC). The biological significance of 5caC largely relates to its role as an intermediate that can be recognized by thymine DNA glycosylase (TDG). TDG excises 5caC from DNA, initiating base excision repair that ultimately restores unmodified cytosine, thereby removing the methylation signal. This cycle contributes to dynamic regulation of methylation patterns across development and cellular differentiation.

Biologically, 5caC is detected at low, but measurable, levels in mammalian genomes and appears to be enriched at specific genomic regions under certain conditions, reflecting the activity of TET enzymes and DNA repair pathways. The exact functional consequences of 5caC presence, beyond its role in demethylation, are an area of ongoing research, including potential effects on chromatin structure and protein-DNA interactions.

Detection and analysis of 5caC employ mass spectrometry and sequencing-based approaches that can distinguish oxidized cytosine derivatives, sometimes following chemical labeling or enzymatic treatment to map their genomic distribution.