Interplay between genetic and epigenetic factors governs common fragile site instability in cancer

Abstract

Common fragile sites (CFSs) are regions within the normal chromosomal structure that were characterized as hotspots for genomic instability in cancer almost 30 years ago. In recent years, many efforts have been made to understand the basis of CFS fragility and their involvement in the genomic signature of instability found in malignant tumors. CFSs are among the first regions to undergo genomic instability during cancer development because of their intrinsic sensitivity to replication stress conditions, which result from oncogene expression. The preferred sensitivity of CFSs to replication stress stems from various mechanisms including: replication fork arrest at AT-rich repeats, origin paucity along large genomic regions, failure in activation of dormant origins, late replication timing, collision between replication and transcription along large genes, all leading to incomplete replication of the CFS region and resulting in chromosomal instability. Here we review shared and unique characteristics of CFSs, their underlying causes and implications, particularly for the development of cancer.

Exploring and exploiting the systemic effects of deregulated replication licensing

“…Their structural characteristics, late-replicating timing and paucity of nearby origins are features that render them susceptible to damage and error-prone repair, fueling genomic instability from the earliest stages of cancer development [65,66]. In many cases, the replication intermediates produced at these loci are hard to repair in the existing cell cycle, and thus are shielded by 53BP1 nuclear bodies and transmitted to the next cell generation (mitotic transmission) in an attempt to be repaired.…”

Perturbations in the Replication Program Contribute to Genomic Instability in Cancer

“…While replication stress results in global instability, large genomic regions spanning a few 100 kilobases, termed common fragile sites (CFSs), are particularly vulnerable to replication stress and are more susceptible to double strand breaks (reviewed in [93]). Though these regions are typically stable under normal conditions, they frequently break under stress.…”

Fragility Extraordinaire: Unsolved Mysteries of Chromosome Fragile Sites

“…However, the requirement for DNA repair is likely linked to a potential underlying defect in DNA replication. Therefore, there appears to be two major factors that underlie fragile site instability: defective DNA initiation/progression and replication-transcription conflicts (Le Tallec et al 2014; Ozeri-Galai et al 2014; Sarni and Kerem 2016). Here, we highlight two major areas with competing models, one regarding the replication defects at fragile sites and the other pertaining to the impact of transcriptional status of large genes on chromosome fragility.…”