Journal
CELL CYCLE
Volume 10, Issue 23, Pages 4039-4046Publisher
TAYLOR & FRANCIS INC
DOI: 10.4161/cc.10.23.18409
Keywords
genome instability; replication fork arrest; replication checkpoint; Werner syndrome protein; common fragile sites
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Funding
- Associazione Italiana per la Ricerca sul Cancro (AIRC)
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Common fragile sites (CFS) are difficult-to-replicate genomic regions that show a high propensity to breakage following certain forms of DNA replication stress. Long considered a fascinating component of human chromosome structure, their relevance for biology is proven by the fact that they are frequently rearranged in cancer cells. Furthermore, CFS were found to be the preferential targets for genome instability in the early stages of human tumorigenesis. In recent years, much progress has been made in understanding the structural features of CFS and the mechanisms that monitor and regulate their integrity. From these studies, it has emerged that their fragility may depend on the abnormally high frequency of fork-stalling events occurring at CFS during DNA replication. Consistently, the ATR-dependent checkpoint together with several proteins involved in response to replication fork stalling have been implicated in maintaining CFS stability. Furthermore, more recent findings propose that the scarcity of replication initiation events within CFS may contribute to their expression upon replication perturbation. This review will focus on the molecular determinants responsible for genomic instability at CFS and the systems used by cells to address this eventuality.
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