Uracil-induced replication stress drives mutations, genome instability, anti-cancer treatment efficacy, and resistance

Abstract

Uracil incorporation into DNA, as a result of nucleotide pool imbalances or cytosine deamination (e.g., through APOBEC3A/3B), can result in replication stress and is the most common source of mutations in cancer and aging. Despite the critical role of uracil in genome instability, cancer development, and cancer therapy, only now is there emerging data on its impact on fundamental processes such as DNA replication and genome stability. Removal of uracil from DNA by base excision repair (BER) can generate a DNA single-strand break (SSB), which can trigger homologous recombination (HR) repair or replication fork collapse and cell death. Unprocessed uracil can also induce replication stress directly and independently of BER by slowing down replication forks, leading to single-stranded DNA (ssDNA) gaps. In this perspective, we review how genomic uracil induces replication stress, the therapeutic implications of targeting uracil-induced vulnerabilities, and potential strategies to exploit these mechanisms in cancer treatment.