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Figure 4: Potential mechanisms of cytosine demethylation. (a) The NER machinery, recruited to the preinitiation complex, can recognize the 5-methyl cytosine (meC) as a NER-specific substrate, in the presence of Gadd45 𝛼 , and eliminate it in a process closely related to the canonical NER process with the incision/excision of the oligonucleotide containing the meC. (b) Another pathway involves two steps; first, the deamination of 5-methylcytosine (meC) to thymine, which involves proteins from Apobec family such as AID or APOBEC1. A role in deamination has been also suggested for DNMTs proteins. Consequently, the impairment of the thymine with the guanine in the opposite strand induces the recruitment of DNA glycosylases such as Mbd4 or TDG that remove thymine through cleavage of the glycosidic bond. Following the action of DNA glycosylases, it remains an apyrimidinic site, which is cleaved by an AP endonuclease such as APE1 and repaired through the polymerase 𝛽 and DNA ligases. NER factors and Gadd45 𝛼 are involved in this mechanism but their roles are not determined. (c) We propose that NER factors control the epigenetic environment of the promoter favouring the demethylation of H3K9 and the methylation of H3K4. Following the action of the NER factors, Apobec proteins and BER factors demethylate the meC in a process similar to (b).