In this report, various aspects of cytosine methylation are analyzed from the standpoint of a unifying functional model. It treats this system as a special mechanism for generating the m⁵C-to-T+C transition mutations in the genome. This mechanism is analyzed in detail: (i) m⁵C deamination during replicative DNA methylation, (ii) repair of occurring G:T mispairs, (iii) evolvement of the new hemimethylated sites in DNA, and (iv) postreplicative methylation of these sites. According to the model proposed, the age-related loss of most m⁵C residues from DNA has been shown for both animal tissues and cell lines. The *CG-to-TG+CA mutations disproportionately contribute to general mutagenesis, and may be a main cause of many human hereditary diseases and cancer. It has been concluded that DNA methylation may be the genetically programmed generator for accumulating mutations responsible for cell aging and cancer.

CONTENTS:

1. Introduction.
2. Replicative and postreplicative DNA methylation.
3. Origin of minor thymine in DNA.
4. DNA methylation as generator of mutations.
4.1. Mechanism of m⁵C -to-T+C substitutions.
4.2. Minor thymine is a result of DNA methylation.
4.3. Is m⁵C loss a result of cytosine methylation?
4.4. Hemimethylated sites in DNA.
4.5. What is “reparative” DNA methylation?
4.6. Postreplicative DNA methylation compensates.
for m⁵C loss, but not completely.
5. Genome loses most of m⁵C over life span.
6. Accumulation of m⁵C-to-T mutations in genome.
7. Conclusion.