O-GlcNAc Misregulation and Aneuploidy in Breast Cancer

We have identified the miR-99 family of microRNAs as being downregulated in more advanced cancer cell lines, having expression that inversely correlates with radiation resistance. The miR-99 family is transiently upgregulated following DNA damage, and when expressed exogenously can sensitize cells to ionizing radiation. Through its target, 5NF2H, the miR-99 family can reduce BRACA1 foci formation at sites of DNA damage, and reduce the rate of DNA repair follow damage by IR. Furthermore, exogenous miR-99a and miR-100 can reduce the overall efficiency of double strand break repair by both homologous recombination as well as non-homologous end joining. When exposed to ionizing radiation, the transient up regulation of the miR-99 family leads to cells less efficiently recruiting BRACA1 to DNA damage foci after repeated exposure to radiation, an effect that is abrogated by antisense inhibition of miR-99 induction. This downregulation of the efficiency of DNA repair may represent a mechanism by which normal cells abort repair and survival after repeated mutagenic events, and whose loss confers resistance to DNA damaging radiation and chemotherapy in advanced cancer cells.