Abstract
The role of common fragile sites (CFSs) in cancer remains controversial. Two main views dominate the discussion: one suggests that CFS loci are hotspots of genomic instability leading to inactivation of genes encoded within them, while the other view proposes that CFSs are functional units and that loss of the encoded genes confers selective pressure, leading to cancer development. The latter view is supported by emerging evidence showing that expression of a given CFS is associated with genome integrity and that inactivation of CFS-resident tumor suppressor genes leads to dysregulation of the DNA damage response (DDR) and increased genomic instability. These two viewpoints of CFS function are not mutually exclusive but rather coexist; when breaks at CFSs are not repaired accurately, this can lead to deletions by which cells acquire growth advantage because of loss of tumor suppressor activities. Here, we review recent advances linking some CFS gene products with the DDR, genomic instability, and carcinogenesis and discuss how their inactivation might represent a selective advantage for cancer cells.
Highlights
Common fragile sites (CFSs) are genomic regions that display breaks, gaps, and constrictions in metaphase chromosomes grown under conditions that impede DNA synthesis, a state known as replication stress (Box 1) [1,2,3]
The prevailing view of CFS biology in the literature has associated their expression with occurrence of uncontrolled breaks or gaps in metaphase chromosomes and their association with human pathologies
This view has been recently challenged by revealing the existence of an active mechanism that is responsible for controlled generation of DNA double strand breaks (DSBs) at CFSs and the evidence that this process enhances, rather than compromises, the maintenance of genome integrity [136]
Summary
Common fragile sites (CFSs) are genomic regions that display breaks, gaps, and constrictions in metaphase chromosomes grown under conditions that impede DNA synthesis, a state known as replication stress (Box 1) [1,2,3]. Two groundbreaking studies proposed a hierarchical model for replication stress, DDR, and CFSs during cancer progression [8, 9], suggesting that an aberrant proliferation in preneoplastic lesions leads to DNA replication stress This replication stress, either directly or through the formation of DSBs, can activate the ATR or ATM DNA-damage checkpoints. Analysis of SNP array data revealed that at early stages of cancer evolution, LOH occurs at CFSs with high frequency, while in more advanced tumors this rate decreases because of widespread genomic instability throughout the genome [10] This difference may derive from progressive loss of CFS-P tumor-suppressor activities, which might provide a direct growth advantage, as well as from the loss of other DDR checkpoint proteins. Consistent with this hypothesis, emerging evidence implicates a number of CFS-Ps in maintenance of the DDR, cell cycle checkpoint, and genome stability (see below)
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
