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

D Hühn; A N Kousholt; Claus Storgaard Sørensen; A A Sartori

doi:10.1038/onc.2014.329

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

D Hühn, A N Kousholt, Claus Storgaard Sørensen, A A Sartori

19 Citationer (Scopus)

Abstract

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.

Originalsprog	Engelsk
Tidsskrift	Oncogene
Vol/bind	0
Sider (fra-til)	3977-3984
Antal sider	8
ISSN	0950-9232
DOI	https://doi.org/10.1038/onc.2014.329
Status	Udgivet - 23 jul. 2015

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10.1038/onc.2014.329

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title = "miR-19, a component of the oncogenic miR-17∼92 cluster, targets the DNA-end resection factor CtIP",

abstract = "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.",

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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 - 2015/7/23

Y1 - 2015/7/23

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.

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.

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DO - 10.1038/onc.2014.329

M3 - Journal article

C2 - 25308476

SN - 0950-9232

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SP - 3977

EP - 3984

JO - Oncogene

JF - Oncogene

ER -

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

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