Methylation status of endogenous DNA double strand breaks: possible connection between genomic hypomethylation and instability

ABSTRACT

Background: DNA methylation and repair of double-strand breaks (DSBs) are crucial for maintaining genomic integrity. In cancer, global hypomethylation leads to genomic instability. Nonetheless, the underlying mechanism(s) has not been identified. Although DSBs can be produced by numerous agents, they also occur spontaneously as endogenous DSBs (EDSBs). Interestingly, methylation levels of EDSBs are higher than at the genomic level. Objectives and methods: I propose a hypothesis as to how EDSBs are hypermethylated and suggest how this hypothesis may connect with the underlying mechanism by which global hypomethylation leads to genomic instability. Results: EDSBs are hypermethylated. EDSB processing is distinct and depends on DNA methylation status. Methylation of EDSBs exists in the genome prior to DNA breaks. There are significant levels of EDSBs in both replicating and non-replicating cells. However, hypermethylation of EDSBs is replication-independent. Ethylated DNA is often associated with heterochromatin and radiation-induced DSB repair may be different depending on chromatin status. There are reports of a unique radiation-induced heterochromatin DNA-repair pathway in nonreplicating cells. A DSB-related histone modification, γ-H2AX, serine-139 phosphorylated form of histone H2AX, is formed less preferentially in heterochromatin after ionizing radiation. Moreover, radiation-induced heterochromatin DSB repair was also shown to be repaired slowly and is Ataxia Telangiectasia Mutated (ATM)- dependent. Therefore, if EDSB repair is similar to radiation-induced DSB repair, methylated EDSB repair may also be dependent on a more precise ATM-dependent non-homologous end-joining repair. Conclusion: The higher methylation level of EDSBs may be due to methylation-dependent EDSB repair. This repair may be slower and thereby possess better precision. Consequently, the increase in the spontaneous mutation rate in the hypomethylated cancer genome may be due to the fact that unmethylated EDSB repair is more error prone.