**5.1 Epigenetic alterations by promoter methylation**

One of the most common ways of epigenetic alteration is by promoter methylation, this is often regulated by cytosine methyl transferases, genes get inactivated by methylation in 5-carbon of cytosine of 5′-CpG-3′ dinucleotide sequence at either promoter regions. Two of the genes involved in base excision repair namely Methyl-CpG Binding Domain 4, DNA (MBD4) and Thymine-DNA glycosylase (TDG), both are glycosylases with same function of removing mismatches by hydrolyzing carbon-nitrogen linkage between the sugar and the phosphate backbone of DNA and mis paired thymine. Due to promoter methylation in these two genes, it is found that BER pathway often gets suppressed in cancers like colorectal, myeloma, ovarian, etc. [41].

The *XPC* gene which encodes a protein that is a key component of the XPC complex involved in GG-NER, promoter methylation of this gene often leads to NER function loss in cancers like bladder cancer. Other genes of the nucleotide excision repair pathway, RAD23A and ERCC1 genes also get inactivated by promoter methylation in different cancers like RAD23A in multiple myeloma cancers and ERCC1 in glioma cancer. Genes of the mismatch repair pathway namely MLH1, MSH2, MSH3, and MSH6 also gets suppressed by promoter methylation in various cancers like ovarian, gastric, etc. [41, 42].

Two genes BRCA1 and BRCA2 of homologous recombination system also have compromised activity by promoter methylation in different cancers like breast, gastric, uterine, etc. One of the genes, involved in non-homologous end-joining, XRCC5 encodes the heterodimer Ku (composed of K70/K80), which facilitates binding to nascent DNA breaks often gets epigenetically inactivated by promoter methylation is seen to be associated with cancers like adenocarcinomas [43]*.*

Direct reversal of DNA damage is the most energy efficient repair system, but its capabilities encompasses only certain damage categories such as pyrimidine dimers formed by UV radiation, O6 adducts like alkyl groups on nucleotides from chemotherapy. *O*6-methylguanine-DNA methyltransferase (MGMT), catalyzes transfer of methyl groups on DNA to its own molecule, methylation on its promoter inactivates it like the other DNA repair genes, this is often associated with cancers like glioblastomas, colon cancer, lung cancer, lymphoma etc. [44].
