@article {323, title = {Editing of Epstein-Barr virus-encoded BART6 microRNAs controls their dicer targeting and consequently affects viral latency.}, journal = {J Biol Chem}, volume = {285}, year = {2010}, month = {2010 Oct 22}, pages = {33358-70}, abstract = {

Certain primary transcripts of miRNA (pri-microRNAs) undergo RNA editing that converts adenosine to inosine. The Epstein-Barr virus (EBV) genome encodes multiple microRNA genes of its own. Here we report that primary transcripts of ebv-miR-BART6 (pri-miR-BART6) are edited in latently EBV-infected cells. Editing of wild-type pri-miR-BART6 RNAs dramatically reduced loading of miR-BART6-5p RNAs onto the microRNA-induced silencing complex. Editing of a mutation-containing pri-miR-BART6 found in Daudi Burkitt lymphoma and nasopharyngeal carcinoma C666-1 cell lines suppressed processing of miR-BART6 RNAs. Most importantly, miR-BART6-5p RNAs silence Dicer through multiple target sites located in the 3\&$\#$39;-UTR of Dicer mRNA. The significance of miR-BART6 was further investigated in cells in various stages of latency. We found that miR-BART6-5p RNAs suppress the EBNA2 viral oncogene required for transition from immunologically less responsive type I and type II latency to the more immunoreactive type III latency as well as Zta and Rta viral proteins essential for lytic replication, revealing the regulatory function of miR-BART6 in EBV infection and latency. Mutation and A-to-I editing appear to be adaptive mechanisms that antagonize miR-BART6 activities.

}, keywords = {Cell Line, Tumor, Epstein-Barr Virus Infections, Epstein-Barr Virus Nuclear Antigens, Gene Silencing, Herpesvirus 4, Human, Humans, Immediate-Early Proteins, MicroRNAs, Ribonuclease III, RNA Editing, RNA, Viral, Trans-Activators, Viral Proteins, Virus Latency}, issn = {1083-351X}, doi = {10.1074/jbc.M110.138362}, author = {Iizasa, Hisashi and Wulff, Bjorn-Erik and Alla, Nageswara R and Maragkakis, Manolis and Megraw, Molly and Hatzigeorgiou, Artemis and Iwakiri, Dai and Takada, Kenzo and Wiedmer, Andreas and Showe, Louise and Lieberman, Paul and Nishikura, Kazuko} } @article {327, title = {Frequency and fate of microRNA editing in human brain.}, journal = {Nucleic Acids Res}, volume = {36}, year = {2008}, month = {2008 Sep}, pages = {5270-80}, abstract = {

Primary transcripts of certain microRNA (miRNA) genes (pri-miRNAs) are subject to RNA editing that converts adenosine to inosine (A--\>I RNA editing). However, the frequency of the pri-miRNA editing and the fate of edited pri-miRNAs remain largely to be determined. Examination of already known pri-miRNA editing sites indicated that adenosine residues of the UAG triplet sequence might be edited more frequently. In the present study, therefore, we conducted a large-scale survey of human pri-miRNAs containing the UAG triplet sequence. By direct sequencing of RT-PCR products corresponding to pri-miRNAs, we examined 209 pri-miRNAs and identified 43 UAG and also 43 non-UAG editing sites in 47 pri-miRNAs, which were highly edited in human brain. In vitro miRNA processing assay using recombinant Drosha-DGCR8 and Dicer-TRBP (the human immuno deficiency virus transactivating response RNA-binding protein) complexes revealed that a majority of pri-miRNA editing is likely to interfere with the miRNA processing steps. In addition, four new edited miRNAs with altered seed sequences were identified by targeted cloning and sequencing of the miRNAs that would be processed from edited pri-miRNAs. Our studies predict that approximately 16\% of human pri-miRNAs are subject to A--\>I editing and, thus, miRNA editing could have a large impact on the miRNA-mediated gene silencing.

}, keywords = {Adenosine, Adenosine Deaminase, Animals, Base Sequence, Brain, Humans, Inosine, Mice, MicroRNAs, Molecular Sequence Data, RNA Editing, RNA Precursors, RNA Processing, Post-Transcriptional, RNA-Binding Proteins}, issn = {1362-4962}, doi = {10.1093/nar/gkn479}, author = {Kawahara, Yukio and Megraw, Molly and Kreider, Edward and Iizasa, Hisashi and Valente, Louis and Hatzigeorgiou, Artemis G and Nishikura, Kazuko} } @article {328, title = {Genomic and epigenetic alterations deregulate microRNA expression in human epithelial ovarian cancer.}, journal = {Proc Natl Acad Sci U S A}, volume = {105}, year = {2008}, month = {2008 May 13}, pages = {7004-9}, abstract = {

MicroRNAs (miRNAs) are an abundant class of small noncoding RNAs that function as negative gene regulators. miRNA deregulation is involved in the initiation and progression of human cancer; however, the underlying mechanism and its contributions to genome-wide transcriptional changes in cancer are still largely unknown. We studied miRNA deregulation in human epithelial ovarian cancer by integrative genomic approach, including miRNA microarray (n = 106), array-based comparative genomic hybridization (n = 109), cDNA microarray (n = 76), and tissue array (n = 504). miRNA expression is markedly down-regulated in malignant transformation and tumor progression. Genomic copy number loss and epigenetic silencing, respectively, may account for the down-regulation of approximately 15\% and at least approximately 36\% of miRNAs in advanced ovarian tumors and miRNA down-regulation contributes to a genome-wide transcriptional deregulation. Last, eight miRNAs located in the chromosome 14 miRNA cluster (Dlk1-Gtl2 domain) were identified as potential tumor suppressor genes. Therefore, our results suggest that miRNAs may offer new biomarkers and therapeutic targets in epithelial ovarian cancer.

}, keywords = {DNA, Neoplasm, Down-Regulation, Epigenesis, Genetic, Epithelial Cells, Female, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Genome, Human, Humans, MicroRNAs, Neoplasm Staging, Ovarian Neoplasms, Ribonuclease III, RNA, Messenger, Survival Analysis}, issn = {1091-6490}, doi = {10.1073/pnas.0801615105}, author = {Zhang, Lin and Volinia, Stefano and Bonome, Tomas and Calin, George Adrian and Greshock, Joel and Yang, Nuo and Liu, Chang-Gong and Giannakakis, Antonis and Alexiou, Pangiotis and Hasegawa, Kosei and Johnstone, Cameron N and Megraw, Molly S and Adams, Sarah and Lassus, Heini and Huang, Jia and Kaur, Sippy and Liang, Shun and Sethupathy, Praveen and Leminen, Arto and Simossis, Victor A and Sandaltzopoulos, Raphael and Naomoto, Yoshio and Katsaros, Dionyssios and Gimotty, Phyllis A and DeMichele, Angela and Huang, Qihong and B{\"u}tzow, Ralf and Rustgi, Anil K and Weber, Barbara L and Birrer, Michael J and Hatzigeorgiou, Artemis G and Croce, Carlo M and Coukos, George} } @article {332, title = {microRNAs exhibit high frequency genomic alterations in human cancer.}, journal = {Proc Natl Acad Sci U S A}, volume = {103}, year = {2006}, month = {2006 Jun 13}, pages = {9136-41}, abstract = {

MicroRNAs (miRNAs) are endogenous noncoding RNAs, which negatively regulate gene expression. To determine genomewide miRNA DNA copy number abnormalities in cancer, 283 known human miRNA genes were analyzed by high-resolution array-based comparative genomic hybridization in 227 human ovarian cancer, breast cancer, and melanoma specimens. A high proportion of genomic loci containing miRNA genes exhibited DNA copy number alterations in ovarian cancer (37.1\%), breast cancer (72.8\%), and melanoma (85.9\%), where copy number alterations observed in \>15\% tumors were considered significant for each miRNA gene. We identified 41 miRNA genes with gene copy number changes that were shared among the three cancer types (26 with gains and 15 with losses) as well as miRNA genes with copy number changes that were unique to each tumor type. Importantly, we show that miRNA copy changes correlate with miRNA expression. Finally, we identified high frequency copy number abnormalities of Dicer1, Argonaute2, and other miRNA-associated genes in breast and ovarian cancer as well as melanoma. These findings support the notion that copy number alterations of miRNAs and their regulatory genes are highly prevalent in cancer and may account partly for the frequent miRNA gene deregulation reported in several tumor types.

}, keywords = {Breast Neoplasms, Female, Gene Dosage, Gene Expression Profiling, Humans, MicroRNAs, Neoplasms, Nucleic Acid Hybridization, Oligonucleotide Array Sequence Analysis, Ovarian Neoplasms, Statistics as Topic}, issn = {0027-8424}, doi = {10.1073/pnas.0508889103}, author = {Zhang, Lin and Huang, Jia and Yang, Nuo and Greshock, Joel and Megraw, Molly S and Giannakakis, Antonis and Liang, Shun and Naylor, Tara L and Barchetti, Andrea and Ward, Michelle R and Yao, George and Medina, Angelica and O{\textquoteright}brien-Jenkins, Ann and Katsaros, Dionyssios and Hatzigeorgiou, Artemis and Gimotty, Phyllis A and Weber, Barbara L and Coukos, George} }