XRN2 is required for the degradation of target RNAs by RNase H1-dependent antisense oligonucleotides.

作者: Shin-Ichiro Hori , Tsuyoshi Yamamoto , Satoshi Obika

DOI: 10.1016/J.BBRC.2015.06.171

关键词: RNase PBiologyRNAMature messenger RNAOligonucleotideMolecular biologyMessenger RNAGeneExoribonucleaseCleavage (embryo)

摘要: Antisense oligonucleotides (ASOs) can suppress the expression of a target gene by cleaving pre-mRNA and/or mature mRNA via RNase H1. Following initial endonucleolytic cleavage H1, RNAs are degraded mechanism that is poorly understood. To better understand this degradation pathway, we depleted two major 5' to 3' exoribonucleases (XRNs), named XRN1 and XRN2, analyzed levels fragments in vitro. We found generated ASO were almost completely from their ends nuclear XRN2 after H1-mediated cleavage, whereas partially XRN2. In contrast ASO, small interference RNA (siRNA) could reduce level only mRNA, fragment was cytoplasmic XRN1. Our findings indicate targeted H1-dependent rapidly nucleus, contrary pathway mediated siRNA.

参考文章(19)
Y Zhang, Z Qu, S Kim, V Shi, B Liao, P Kraft, R Bandaru, Y Wu, L M Greenberger, I D Horak, Down-modulation of cancer targets using locked nucleic acid (LNA)-based antisense oligonucleotides without transfection. Gene Therapy. ,vol. 18, pp. 326- 333 ,(2011) , 10.1038/GT.2010.133
P. C. Zamecnik, M. L. Stephenson, Inhibition of Rous sarcoma virus replication and cell transformation by a specific oligodeoxynucleotide Proceedings of the National Academy of Sciences of the United States of America. ,vol. 75, pp. 280- 284 ,(1978) , 10.1073/PNAS.75.1.280
Vinay K. Nagarajan, Christopher I. Jones, Sarah F. Newbury, Pamela J. Green, XRN 5′→3′ exoribonucleases: Structure, mechanisms and functions Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms. ,vol. 1829, pp. 590- 603 ,(2013) , 10.1016/J.BBAGRM.2013.03.005
Takashi S. Miki, Helge Großhans, The multifunctional RNase XRN2 Biochemical Society Transactions. ,vol. 41, pp. 825- 830 ,(2013) , 10.1042/BST20130001
Alexei A. Koshkin, Sanjay K. Singh, Poul Nielsen, Vivek K. Rajwanshi, Ravindra Kumar, Michael Meldgaard, Carl Erik Olsen, Jesper Wengel, LNA (Locked Nucleic Acids): Synthesis of the adenine, cytosine, guanine, 5-methylcytosine, thymine and uracil bicyclonucleoside monomers, oligomerisation, and unprecedented nucleic acid recognition Tetrahedron. ,vol. 54, pp. 3607- 3630 ,(1998) , 10.1016/S0040-4020(98)00094-5
Hongjiang Wu, Walt F. Lima, Hong Zhang, Amy Fan, Hong Sun, Stanley T. Crooke, Determination of the role of the human RNase H1 in the pharmacology of DNA-like antisense drugs. Journal of Biological Chemistry. ,vol. 279, pp. 17181- 17189 ,(2004) , 10.1074/JBC.M311683200
Mark J. Graham, Kristina M. Lemonidis, Charles P. Whipple, Amuthakannan Subramaniam, Brett P. Monia, Stanley T. Crooke, Rosanne M. Crooke, Antisense inhibition of proprotein convertase subtilisin/kexin type 9 reduces serum LDL in hyperlipidemic mice Journal of Lipid Research. ,vol. 48, pp. 763- 767 ,(2007) , 10.1194/JLR.C600025-JLR200
R. Y. Walder, J. A. Walder, Role of RNase H in hybrid-arrested translation by antisense oligonucleotides Proceedings of the National Academy of Sciences of the United States of America. ,vol. 85, pp. 5011- 5015 ,(1988) , 10.1073/PNAS.85.14.5011
M. L. Stephenson, P. C. Zamecnik, Inhibition of Rous sarcoma viral RNA translation by a specific oligodeoxyribonucleotide Proceedings of the National Academy of Sciences of the United States of America. ,vol. 75, pp. 285- 288 ,(1978) , 10.1073/PNAS.75.1.285
Tsuyoshi Yamamoto, Moeka Nakatani, Keisuke Narukawa, Satoshi Obika, Antisense drug discovery and development Future Medicinal Chemistry. ,vol. 3, pp. 339- 365 ,(2011) , 10.4155/FMC.11.2