The DOI matches its Crossref record; 4 of the 4 references it cites were found in a registry or an index.
siRNA-mediated off-target gene silencing triggered by a 7 nt complementation
Open accessAbstract
A growing body of evidence suggests that siRNA could generate off-target effects through different mechanisms. However, the full impact of off-target gene regulation on phenotypic induction and accordingly on data interpretation in the context of large-scale siRNA library screen has not been reported. Here we report on off-target gene silencing effects observed in a large-scale knockdown experiment designed to identify novel regulators of the HIF-1 pathway. All of the three 'top hits' from our screen have been demonstrated to result from off-target gene silencing. Two of the three 'siRNA hits' were found to directly trigger down-regulation of hif-1alpha mRNA through a 7 nt motif, AGGCAGT, that is present in both the hif-1alpha mRNA and the siRNAs. Further analysis revealed that the generation of off-target gene silencing via this 7 nt motif depends on the characteristics of the target mRNA, including the sequence context surrounding the complementary region, the position of the complementary region in the mRNA and the copy number of the complementary region. Interestingly, the off-target siRNA against hif-1alpha was also shown to trigger mRNA degradation with high probability of other genes that possess multiple copies of the AGGCAGT motif in the 3'-untranslated region. Lessons learned from this study will be a valuable asset to aid in designing siRNAs with more stringent target selectivity and improving 'hits-follow-up' strategies for future large-scale knockdown experiments.
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Cites
Targeting HIF-1 for cancer therapy
Semenza, G. L. (2003) · Nature Reviews Cancer · doi:10.1038/nrc1187 · Cited by 6,717
Prediction of Mammalian MicroRNA Targets
Lewis, B. P., Shih, I.-H., Jones-Rhoades, M. W., Bartel, D. P., & Burge, C. B. (2003) · Cell · doi:10.1016/s0092-8674(03)01018-3 · Cited by 5,199
Hypoxia — a key regulatory factor in tumour growth
Harris, A. L. (2002) · Nature Reviews Cancer · doi:10.1038/nrc704 · Cited by 5,177
Expression profiling reveals off-target gene regulation by RNAi
Jackson, A. L., Bartz, S. R., Schelter, J., Kobayashi, S. V., Burchard, J., Mao, M., Li, B., Cavet, G., & Linsley, P. S. (2003) · Nature Biotechnology · doi:10.1038/nbt831 · Cited by 2,370
Cited by
RNAi therapeutics: a potential new class of pharmaceutical drugs
Bumcrot, D., Manoharan, M., Koteliansky, V., & Sah, D. W. Y. (2006) · Nature Chemical Biology · doi:10.1038/nchembio839 · Cited by 1,085
Jackson, A. L., & Linsley, P. S. (2010) · Nature Reviews Drug Discovery · doi:10.1038/nrd3010 · Cited by 1,083
siRNA versus miRNA as therapeutics for gene silencing
Lam, J. K. W., Chow, M. Y. T., Zhang, Y., & Leung, S. W. S. (2015) · Molecular Therapy — Nucleic Acids · doi:10.1038/mtna.2015.23 · Cited by 1,081
3′ UTR seed matches, but not overall identity, are associated with RNAi off-targets
Birmingham, A., Anderson, E. M., Reynolds, A., Ilsley-Tyree, D., Leake, D., Fedorov, Y., Baskerville, S., Maksimova, E., Robinson, K., Karpilow, J., et al. (2006) · Nature Methods · doi:10.1038/nmeth854 · Cited by 920
RNAi therapeutics: Principles, prospects and challenges
Aagaard, L., & Rossi, J. J. (2007) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2007.03.005 · Cited by 895
Metadata
- Authors
- Lin, X.
- Venue
- Nucleic Acids Research
- Publisher
- Oxford University Press (OUP)
- Published
- 2005-08-02
- Volume
- 33
- Issue
- 14
- Pages
- 4527-4535
- ISSN
- 0305-1048 (ISSN-L)
- 1362-4962
- OpenAlex
- W2047922381
- Cited by
- 368
- References
- 4
- FWCI
- 12.33
- Type
- journal article
- Language
- en
- Open access
- gold
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