DNA replication and oncogene-induced replicative stress

Abstract

DNA replication must be tightly regulated to ensure that the genome is accurately duplicated during each cell cycle. When these regulatory mechanisms fail, replicative stress and DNA damage ensue. Activated oncogenes promote replicative stress, inducing a DNA damage response (DDR) early in tumorigenesis. Senescence or apoptosis result, forming a barrier against tumour progression. This may provide a selective pressure for acquisition of mutations in the DDR pathway during tumorigenesis. Despite its potential importance in early cancer development, the precise nature of oncogene-induced replicative stress remains poorly understood. Here, we review our current understanding of replication initiation and its regulation, describe mechanisms by which activated oncogenes might interfere with these processes and discuss how replicative stress might contribute to the genomic instability seen in cancers.