The miR-99 family regulates the DNA damage response through its target SNF2H

Chromatin remodeling factors are becoming known as crucial facilitators of recruitment of repair proteins to sites of DNA damage. Multiple chromatin remodeling protein complexes are now known to be required for efficient double strand break repair. In a screen for microRNAs (miRNAs) that modulate the DNA damage response, we discovered that expression of the miR-99 family of miRNAs correlates with radiation sensitivity. These miRNAs were also transiently induced following radiation. The miRNAs target the SWI/SNF chromatin remodeling factor SNF2H/SMARCA5, a component of the ACF1 complex. We found that by reducing levels of SNF2H, miR-99a and miR-100 reduced BRCA1 localization to sites of DNA damage. Introduction of the miR-99 family of miRNAs into cells reduced the rate and overall efficiency of repair by both homologous recombination and non-homologous end joining. Finally, induction of the miR-99 family following radiation prevents an increase in SNF2H expression and reduces the recruitment of BRCA1 to the sites of DNA damage following a second dose of radiation, reducing the efficiency of repair after multiple rounds of radiation, as used in fractionated radiotherapy.