MiRNAs Targeting Double Strand DNA Repair Pathways Lurk in Genomically Unstable Rare Fragile Sites and Determine Cancer Outcomes

Double strand break (DSB) repair mechanisms guard genome integrity and their deterioration causes genomic instability. Common and rare fragile sites (CFS and RFS, respectively) are particularly vulnerable to instability, and there is an inverse correlation between fragile site (FS) expression and DSB repair protein levels. Upon DSB repair dysfunction, genes residing at these sites are at greater risk of deregulation compared to genes located at non-FS. In this regard, it remains enigmatic why the incidence of miRNA genes at FS is higher compared to non-FS. Herein, using bioinformatics, we examined whether miRNA genes localized at FS inhibit components of DSB repair pathways and assessed their effects on cancer. We show that such miRNAs over-accumulate in RFS, and that FRAXA, which is expressed in Fragile X syndrome, is a conserved hotspot for miRNAs inhibiting DSB repair. Axes of FRAXA-residing miRNAs/DSB repair targets affect survival in a cancer type-specific manner. Moreover, copy number variations in the region encompassing these miRNA genes discriminate survival between male and female patients. Given that, thus far, only CFS have been considered relevant for carcinogenesis, our data are the first to associate RFS with cancer, through the impairment of DSB repair by the FRAXA-residing miRNAs.