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.