DNA replication stress drives fragile site instability
Abstract DNA replication stress is one of the early drivers enabling the ongoing acquisition of genetic changes arising during tumorigenesis. As such, it is a feature of most pre-malignant and malignant cells. In this review article, we focus on the early events initiating DNA replication stress and the preferential sensitivity of common fragile sites (CFSs) to this stress. CFSs are specific genomic regions within the normal chromosomal structure, which appear as gaps and breaks in the metaphase chromosomes of cells grown under mild replication stress conditions. The main characteristics predisposing CFSs to instability include late replication timing, delayed replication completion, failure to activate additional origins, origin paucity along large genomic regions, collision between replication and transcription complexes along large genes, and the presence of AT-dinucleotide rich sequences. The contribution of these features to instability at CFSs during early cancer development is discussed. Highlights DNA replication stress drives genome instability and initiates tumorigenicity. Nucleotide deficiency and deregulated origin firing lead to replication stress. CFSs exhibit intrinsic sensitivity to replication stress conditions. Under stress the replication along CFSs is delayed and even uncompleted. CFSs are preferentially unstable in pre-cancerous lesions and during cancer development.
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