Endogenous Sources of Abasic Sites and Implications for DNA Replication: Mechanisms of Fork Stalling and Recovery

Apurinic/apyrimidinic (AP) sites, also known as abasic sites, are among the most frequent DNA lesions, arising spontaneously or as intermediates in base excision repair. Their structural impediment to DNA replication fork progression, lack of coding information, and conversion into strand breaks constitute a threat and can lead to genome instability if not properly managed. This review examines the impact of AP sites on DNA replication, detailing mechanisms of lesion bypass, including translesion synthesis, template switching, and repriming of DNA synthesis. We highlight protective pathways that shield AP sites from nucleolytic attack and explore how endogenous processes such as uracil excision, cytosine methylation, and oxidative damage generate these lesions. By integrating biochemical and cellular perspectives, we present a comprehensive view of how cells replicate their DNA in the presence of AP sites and how their mismanagement contributes to replication stress, mutagenesis, and disease.