Global hypomethylation may potentially promote carcinogenesis via at least three possible mechanisms: activation of oncogenes, reactivation of transposable elements and genomic instability. The thesis aims to study the mechanism of global hypomethylation induces genomic instability. We hypothesized whether global hypomethylation induces instability in trans by reactivated LINE-1 retrotranspositional activity. We established a new technique to map and screen for new LINE-1 insertions, called “LIDSIP”. The PCR was applied to compare between cervical cancer and normal cells from the same patients. However, we discovered that LINE-1 retrotransposition is rare and should not be the major mechanism of cervical cancer mutations. Therefore, we evaluated our second hypothesis that genomic instability is related to DNA methylation in cis. This mechanism may depend on how DNA methylation is related to how endogenous DNA double-stranded breaks (EDSBs) are produced or repaired. We developed a set of new techniques for quantification of EDSBs and methylation levels of genome and EDSBs. The aims of these techniques were to investigate whether global hypomethylation induces genomic instability in cis via EDSBs. Therefore, EDBS methylation statuses should be association with this mechanism. Our study discovered that DNA breakages are commonly retained event under normal physiologic circumstance and the quantity of retained EDSBs is cell types specific. The majority of retained EDSBs are methylated. Nonetheless, methylated EDSBs are eventually repaired. A defect in Ataxia Telangiectasia Mutated (ATM) repair raised the EDSB methylation level. Therefore, methylated EDSB repair is dependent on ATM dependent precise repair pathways. In conclusion, unmethylated and methylated EDSBs preferentially undergo different repair pathways. Consequently, increase of spontaneous mutation rate due to the genomic hypomethylation level may be related to how methylated and unmethylated EDSBs are differentially processed.