Abstract
Genomic instability, a hallmark of cancer, occurs preferentially at specific genomic regions known as common fragile sites (CFSs). CFSs are evolutionarily conserved and late replicating regions with AT-rich sequences, and CFS instability is correlated with cancer. In the last decade, much progress has been made toward understanding the mechanisms of chromosomal instability at CFSs. However, despite tremendous efforts, identifying a cancer-associated CFS gene (CACG) remains a challenge and little is known about the function of CACGs at most CFS loci. Recent studies of FATS (for Fragile-site Associated Tumor Suppressor), a new CACG at FRA10F, reveal an active role of this CACG in regulating DNA damage checkpoints and suppressing tumorigenesis. The identification of FATS may inspire more discoveries of other uncharacterized CACGs. Further elucidation of the biological functions and clinical significance of CACGs may be exploited for cancer biomarkers and therapeutic benefits.
Highlights
Common fragile sites (CFSs) are specific chromosomal regions that preferentially form gaps or breaks on metaphase chromosomes under replication stress
A genetic assay showed that a short AT-rich region within FRA16D causes increased chromosome breakage by forming strong secondary structures that stall replication fork progression [29], supporting the argument that repeat instability is an important and unique form of mutation that is linked to neurodegenerative disorders caused by expansion of trinucleotide repeats at rare fragile sites [30], and linked to CFS fragility caused by tandem repeat sequences, including AT-dinucleotide repeats
Microarray-based studies of mouse tumor models (Figure 1) reveals the tumor suppressor gene CDKN2A (p16) at a frequently deleted region in tumors induced by Ionizing radiation (IR). These results demonstrated the reliability of the microarray-based approach in mouse tumor models, which led to the discovery of the FATS tumor suppressor gene
Summary
Common fragile sites (CFSs) are specific chromosomal regions that preferentially form gaps or breaks on metaphase chromosomes under replication stress. Not all CFSs form breaks or gaps at the same frequency [6], and two sites (FRA3B and FRA16D) in the human genome are most prone to form lesions. A hallmark of cancer, occurs preferentially at CFSs. the study of CFSs can provide insight into carcinogenesis, and lead to the discovery of new cancer-related genes. We will review recent advances in the field of cancer-related CFSs. We describe the efforts in mapping FRA10F and identification of a new CFS gene, named FATS
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