miR-19, a component of the oncogenic miR-17 similar to 92 cluster, targets the DNA-end resection factor CtIP

• Published in: Oncogene 2015-07, Vol.34 (30), p.3977-3984
• Main Authors: Huehn, D, Kousholt, A N, Soerensen, C S, Sartori, A A
• Format: Article
• Language: English
• ISSN: 0950-9232
• DOI: 10.1038/onc.2014.329

MicroRNA-19 (miR-19) was recently identified as the key oncogenic component of the polycistronic miR-17 similar to 92 cluster, also known as oncomiR-1, which is frequently upregulated or amplified in multiple tumor types. However, the gene targets and the pathways underlying the tumor-promoting activity of miR-19 still remain largely elusive. CtIP/RBBP8 promotes DNA-end resection, a critical step in the repair of DNA double-strand breaks (DSBs) by homologous recombination (HR), and is considered to function as a tumor suppressor. In this study, we show that miR-19 downregulates CtIP expression by binding to two highly conserved sequences located in the 3'-untranslated region of CtIP mRNA. We further demonstrate that CtIP expression is repressed by miR-19 during continuous genotoxic stress in a p53-dependent manner. Finally, we report that miR-19 impairs CtIP-mediated DNA-end resection, which results in reduced HR levels and DNA damage hypersensitivity. By downregulating CtIP, miR-19 overexpression suppresses the faithful repair of DSBs that is crucial for genome maintenance. Our findings thus provide new mechanistic insight into the oncogenic role of the miR-17 similar to 92 cluster.