Sequences nearby RIND-EDSBs are hypermethylated, and RIND-EDSBs are retained in heterochromatin and preferentially repaired by different pathways. A diagrammatic representation of RIND-EDSBs under normal physiological conditions showing the differences between hyper- and hypomethylated DNA, which associate with hetero- and euchromatin , respectively. RIND-EDSBs are frequently present near methylated DNA . While methylated L1-RIND-EDSBs are concealed in heterochromatin, the earliest DSB repair response, γ-H2AX deposition on chromatin, is more prevalent in hypomethylated DNA. The differential NHEJ repair pathways in non-replicating cells between hyper- and hypomethylated DNA are shown. ATM-mediated end-joining repair prefers methylated EDSBs and more precisely repairs breaks than other mechanisms . NHEJ pathways at hypomethylated genomes may be similar to the processes that repair radiation-induced DSBs in that the repair processes are interchangeable [64, 66, 67]. Other error-prone, less known and redundant pathways are not included in the diagram. However, these pathways may be prevented from repairing methylated RIND-EDSBs. Spontaneous mutations accumulate more quickly in hypomethylated regions of the genome [9, 10, 15].