%0 Journal Article %J J Biol Chem %D 2010 %T Editing of Epstein-Barr virus-encoded BART6 microRNAs controls their dicer targeting and consequently affects viral latency. %A Iizasa, Hisashi %A Wulff, Bjorn-Erik %A Alla, Nageswara R %A Maragkakis, Manolis %A Megraw, Molly %A Hatzigeorgiou, Artemis %A Iwakiri, Dai %A Takada, Kenzo %A Wiedmer, Andreas %A Showe, Louise %A Lieberman, Paul %A Nishikura, Kazuko %K Cell Line, Tumor %K Epstein-Barr Virus Infections %K Epstein-Barr Virus Nuclear Antigens %K Gene Silencing %K Herpesvirus 4, Human %K Humans %K Immediate-Early Proteins %K MicroRNAs %K Ribonuclease III %K RNA Editing %K RNA, Viral %K Trans-Activators %K Viral Proteins %K Virus Latency %X

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'-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.

%B J Biol Chem %V 285 %P 33358-70 %8 2010 Oct 22 %G eng %N 43 %R 10.1074/jbc.M110.138362 %0 Journal Article %J Proc Natl Acad Sci U S A %D 2006 %T microRNAs exhibit high frequency genomic alterations in human cancer. %A Zhang, Lin %A Huang, Jia %A Yang, Nuo %A Greshock, Joel %A Megraw, Molly S %A Giannakakis, Antonis %A Liang, Shun %A Naylor, Tara L %A Barchetti, Andrea %A Ward, Michelle R %A Yao, George %A Medina, Angelica %A O'brien-Jenkins, Ann %A Katsaros, Dionyssios %A Hatzigeorgiou, Artemis %A Gimotty, Phyllis A %A Weber, Barbara L %A Coukos, George %K Breast Neoplasms %K Female %K Gene Dosage %K Gene Expression Profiling %K Humans %K MicroRNAs %K Neoplasms %K Nucleic Acid Hybridization %K Oligonucleotide Array Sequence Analysis %K Ovarian Neoplasms %K Statistics as Topic %X

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.

%B Proc Natl Acad Sci U S A %V 103 %P 9136-41 %8 2006 Jun 13 %G eng %N 24 %R 10.1073/pnas.0508889103