Cells must faithfully duplicate their DNA in the genome to pass their genetic information to the daughter cells.To maintain genomic stability and integrity, double-strand DNA has to be replicated in a strictly regulated manner, ensuring the accuracy of its copy number, integrity and epigenetic modifications.However, DNA is constantly under the attack of DNA Flat Cap damage, among which oxidative DNA damage is the one that most frequently occurs, and can alter the accuracy of DNA replication, integrity and epigenetic features, resulting in DNA replication stress and subsequent genome and epigenome instability.In this review, we summarize DNA damage-induced replication stress, the formation of DNA secondary structures, peculiar epigenetic modifications and cellular responses to the stress and their impact on the SAMSUNG BRB260031WW/EU Integrated No Frost 70/30 195L Fridge 74L Freezer instability of the genome and epigenome mainly in eukaryotic cells.