Targeting DNA-PKcs and ATM with miR-101 sensitizes tumors to radiation.
BACKGROUND
Radiotherapy kills tumor-cells by inducing DNA double strand breaks (DSBs). However, the efficient repair of tumors frequently prevents successful treatment. Therefore, identifying new practical sensitizers is an essential step towards successful radiotherapy. In this study, we tested the new hypothesis: identifying the miRNAs to target DNA DSB repair genes could be a new way for sensitizing tumors to ionizing radiation.


RESULTS
HERE, WE CHOSE TWO GENES: DNA-PKcs (an essential factor for non-homologous end-joining repair) and ATM (an important checkpoint regulator for promoting homologous recombination repair) as the targets to search their regulating miRNAs. By combining the database search and the bench work, we picked out miR-101. We identified that miR-101 could efficiently target DNA-PKcs and ATM via binding to the 3'- UTR of DNA-PKcs or ATM mRNA. Up-regulating miR-101 efficiently reduced the protein levels of DNA-PKcs and ATM in these tumor cells and most importantly, sensitized the tumor cells to radiation in vitro and in vivo.


CONCLUSIONS
These data demonstrate for the first time that miRNAs could be used to target DNA repair genes and thus sensitize tumors to radiation. These results provide a new way for improving tumor radiotherapy.
Yan
Dan
D
Department of Radiation Oncology, Emory University School of Medicine, Winship Cancer Institute of Emory University, Atlanta, Georgia, United States of America.
Ng
Wooi Loon
WL
Zhang
Xiangming
X
Wang
Ping
P
Zhang
Zhaobin
Z
Mo
Yin-Yuan
YY
Mao
Hui
H
Hao
Chunhai
C
Olson
Jeffrey J
JJ
Curran
Walter J
WJ
Wang
Ya
Y
D020413:3' Untranslated Regions / Q000235:genetics; D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins; D001483:Base Sequence; D018797:Cell Cycle Proteins / Q000235:genetics*; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000528:radiation effects; D051747:DNA-Activated Protein Kinase / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D006801:Humans; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D009369:Neoplasms / Q000235:genetics* / Q000473:pathology / Q000532:radiotherapy*; D009687:Nuclear Proteins / Q000235:genetics*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D025521:Tumor Suppressor Proteins / Q000235:genetics*; D015854:Up-Regulation / Q000235:genetics
D020413:3' Untranslated Regions; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C534072:MIRN101 microRNA, human; D035683:MicroRNAs; D009687:Nuclear Proteins; D025521:Tumor Suppressor Proteins; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D051747:DNA-Activated Protein Kinase; C497264:Prkdc protein, mouse; D017346:Protein Serine-Threonine Kinases