title: Understanding the molecular basis of common fragile sites instability: role of the proteins involved in the recovery of stalled replication forks.
abstract: 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 the reason for their fragility may depend on the abnormal 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.
authors.affiliation: Department of Environment and Primary Prevention, Istituto Superiore di Sanità, Rome, Italy. annapaola.franchitto@iss.it
authors.forename: Annapaola
authors.initials: A
authors.lastname: Franchitto
authors.forename: Pietro
authors.initials: P
authors.lastname: Pichierri
mesh_terms: D064007:Ataxia Telangiectasia Mutated Proteins; D059447:Cell Cycle Checkpoints; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D043171:Chromosomal Instability; D043283:Chromosome Fragile Sites; D002877:Chromosomes, Human / Q000235:genetics / Q000378:metabolism; D004260:DNA Repair; D004261:DNA Replication; D015894:Genome, Human; D006801:Humans; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D018741:Replication Origin; D013312:Stress, Physiological; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism
chemical_list: D018797:Cell Cycle Proteins; C111164:BRAP protein, human; D044767:Ubiquitin-Protein Ligases; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases