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Nature Reviews Genetics 5 ; 631(2004); doi:10.1038/nrg1415 MicroRNAs: small RNAs with a big role in gene regulation

Nature Reviews Genetics 5 ; 631(2004); doi:10.1038/nrg1415 MicroRNAs: small RNAs with a big role in gene regulation. Figure 2 |  The current model for the biogenesis and post-transcriptional suppression of microRNAs and small interfering RNAs.

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Nature Reviews Genetics 5 ; 631(2004); doi:10.1038/nrg1415 MicroRNAs: small RNAs with a big role in gene regulation

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  1. Nature Reviews Genetics5; 631(2004); doi:10.1038/nrg1415 MicroRNAs: small RNAs with a big role in gene regulation

  2. Figure 2 | The current model for the biogenesis and post-transcriptional suppression of microRNAs and small interfering RNAs. Nature Reviews Genetics5; 631(2004); doi:10.1038/nrg1415MicroRNAs: small RNAs with a big role in gene regulation

  3. miRNAs and siRNAs — what's the difference? microRNAs 1. Derived from an endogenous, structured transcript (pre-miRNA) 2. One miRNA accumulates 3. Evolutionary conserved 4. Usually located away from genes 5. Imperfect pairing blocks translation 6. Incorporated into miRNP 7. Regulate expression of genes encoded at another locus 8. miRNAs bind to the target 3' UTRs through imperfect complementarity at multiple sites siRNAs 1. Derived from extended dsRNA 2. Each dsRNA gives multiple siRNAs 3. Less conservation 4. Nearly complementary to target RNA (self-targeting) 5. Perfect pairing induces target RNA cleavage 6. Incorporated into RISC 7. Regulate the locus from which their sequence derives 8. siRNAs often form a perfect duplex with their targets at only one site.

  4. Figure 1 |  The molecular hallmarks of lin-4, the founding member of the microRNA family.

  5. Fig. 1: C. elegans worms that contain mutations in the let-7 miRNA gene develop abnormally, often rupturing at the midsection. The let-7 miRNA is expressed in most animals, including humans, where it may also play an essential role in regulating development.

  6. Human microRNA genes are frequently located at fragile sites and genomic regions involved in cancers George Adrian Calin*†, Cinzia Sevignani*†, Calin Dan Dumitru*, Terry Hyslop‡, Evan Noch*, Sai Yendamuri*, Masayoshi Shimizu*, Sashi Rattan*, Florencia Bullrich*, Massimo Negrini*§, and Carlo M. Croce*¶ PNAS2004 Fig. 1. Correlation between FRAs and miRs. A karyotype showing the position of 113 FRAs and 186 miRs is presented. The 61 miRs located in the same chromosomal band as the FRA are red. We were able to precisely locate 35 miRs inside 12 cloned FRAs. The red arrow shows frequently observed FRAs

  7. Human microRNA genes are frequently located at fragile sites and genomic regions involved in cancers George Adrian Calin*†, Cinzia Sevignani*†, Calin Dan Dumitru*, Terry Hyslop‡, Evan Noch*, Sai Yendamuri*, Masayoshi Shimizu*, Sashi Rattan*, Florencia Bullrich*, Massimo Negrini*§, and Carlo M. Croce*¶ PNAS2004 Possible correlations between the genomic position of a large number of miRs and the location of cancer-associated genomic regions??? Fig. 3. MiRs as cancer players. Some of these proposed mechanisms are experimentally proven, like the HD of miR-15amiR-16a cluster in B-CLL (9), the c-myc overexpression by the reposition near a putative miR promoter, or miR143miR-145 cluster down-regulation in colon cancers (39).

  8. Table 2. Examples of miRs located in minimal deleted regions, minimal amplified regions, and breakpoint regions involved in human cancers

  9. Evolutionary Conservation of miRNAs • miRNAs are evolutionary conserved even across phyla • This suggests ancient and important roles for this class of regulators • Observation: Found in multicellular plants and animals but not in unicellular eukaryotes • Question: How many of these tiny regulators are hidden in animal genomes?

  10. Correlations between miRNAs and Disease Calin et al. (2002) Frequent deletions and down-regulation of micro-RNA genes miR15 and miR16 at 13q14 in chronic lymphocytic leukemia. Proc. Nat. Aca. Sci. 99, 15524-9. Caudy AA, Myers M, Hannon GJ, Hammond SM. (2002) Fragile X-related protein and VIG associate with the RNA interference machinery. Genes Dev. 16, 2491-6. Chapman EJ, Prokhnevsky AI, Gopinath K, Dolja VV, Carrington JC. (2004) “ Viral RNA silencing suppressors inhibit the microRNA pathway at an intermediate step,” Genes Dev. 18(10):1179-86. [Abstract] Chen J, Li WX, Xie D, Peng JR, Ding SW. (2004) “ Viral Virulence Protein Suppresses RNA Silencing-Mediated Defense but Upregulates the Role of MicroRNA in Host Gene Expression,” Plant Cell. 16(5):1302-13. [Abstract] Dostie J, Mourelatos Z, Yang M, Sharma A, Dreyfuss G. (2003) Numerous microRNPs in neuronal cells containing novel microRNAs. RNA. 9(2):180-6. Erratum in: RNA. 9, 631-2. Jin P, Zarnescu DC, Ceman S, Nakamoto M, Mowrey J, Jongens TA, Nelson DL, Moses K, Warren ST. (2003) “ Biochemical and genetic interaction between the fragile X mental retardation protein and the microRNA pathway,” Nat Neurosci. 7(2):113-7 [Abstract] McManus MT. (2003) “ MicroRNAs and cancer,” Semin Cancer Biol. 13(4):253-8. [Abstract] Metzler M, Wilda M, Busch K, Viehmann S, Borkhardt A. (2003) “ High expression of precursor microRNA-155/BIC RNA in children with Burkitt lymphoma,” Genes Chromosomes Cancer. 39(2):167-9. [Abstract] Michael MZ, O'Connor SM, van Holst Pellekaan NG, Young GP, James RJ (2003) Reduced accumulation of specific microRNAs in colorectal neoplasia. Molecular Cancer Research 1, 882-91. Takamizawa J, Konishi H, Yanagisawa K, Tomida S, Osada H, Endoh H, Harano T, Yatabe Y, Nagino M, Nimura Y, Mitsudomi T, Takahashi T. Reduced expression of the let-7 microRNAs in human lung cancers in association with shortened postoperative survival. Cancer Res. 2004 Jun 1;64(11):3753-6. [Abstract]

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