miR-19, a component of the oncogenic miR-17∼92 cluster, targets the DNA-end resection factor CtIP
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miR-19, a component of the oncogenic miR-17∼92 cluster, targets the DNA-end resection factor CtIP. / Hühn, D; Kousholt, A N; Sørensen, Claus Storgaard; Sartori, A A.
I: Oncogene, Bind 0, 2015, s. 3977-3984.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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T1 - miR-19, a component of the oncogenic miR-17∼92 cluster, targets the DNA-end resection factor CtIP
AU - Hühn, D
AU - Kousholt, A N
AU - Sørensen, Claus Storgaard
AU - Sartori, A A
PY - 2015
Y1 - 2015
N2 - MicroRNA-19 (miR-19) was recently identified as the key oncogenic component of the polycistronic miR-17∼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∼92 cluster.Oncogene advance online publication, 13 October 2014; doi:10.1038/onc.2014.329.
AB - MicroRNA-19 (miR-19) was recently identified as the key oncogenic component of the polycistronic miR-17∼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∼92 cluster.Oncogene advance online publication, 13 October 2014; doi:10.1038/onc.2014.329.
U2 - 10.1038/onc.2014.329
DO - 10.1038/onc.2014.329
M3 - Journal article
C2 - 25308476
VL - 0
SP - 3977
EP - 3984
JO - Oncogene
JF - Oncogene
SN - 0950-9232
ER -
ID: 138141004