There is an increasing understanding of the roles that microsatellite instability （MSI） plays in Lynch syndrome （by mutations） and sporadic （by mainly epigenetic changes） gastrointestinal （GI） and other cancer...There is an increasing understanding of the roles that microsatellite instability （MSI） plays in Lynch syndrome （by mutations） and sporadic （by mainly epigenetic changes） gastrointestinal （GI） and other cancers. Defi- cient DNA mismatch repair （MMR） results in the strong mutator phenotype known as MSI, which is the hall- mark of cancers arising within Lynch syndrome. MSI is characterized by length alterations within simple repeated sequences called microsatellites. Lynch syn- drome occurs primarily because of germline mutations in one of the MMR genes, mainly MLH1 or MSH2, less frequently MSH6, and rarely PMS2. MSI is also observed in about 15% of sporadic colorectal, gastric, and en-dometrial cancers and in lower frequencies in a minor- ity of other cancers where it is often associated with the hypermethylation of the IVlLH1 gene. miRNAs are small noncoding RNAs that regulate gene expression at the posttranscriptional level and are critical in many biological processes and cellular pathways. There is accumulating evidence to support the notion that the interrelationship between MSI and miRNA plays a key role in the pathogenesis of GI cancer. As a possible new mechanism underlying MSI, overexpression of m/R-IEE has been shown to downregulate expression of MLH1, IVlSH2, and MSH6. Thus, a subset of MSI-positive （MSI＋） cancers without known MMR defects may result from m/R-1E5 overexpression. Target genes of frameshift mutation for MSI are involved in various cellular func- tions, such as DNA repair, cell signaling, and apoptosis. A novel class of target genes that included not only epi- genetic modifier genes, such as HDAC2, but also miRNA processing machinery genes, including TARBP2 and XPO5, were found to be mutated in MSI＋ GI cancers. Thus, a subset of MSI＋ colorectal cancers （CRCs） has been proposed to exhibit a mutated miRNA machinery phenotype. Genetic, epigenetic, and transcriptomic dif- ferences exist between MSI＋ and MSI- cancers. Mo- lecular signatures of miRNA expression apparently have the potential to distinguish between MSI＋ and MSI- CRCs. In this review, we summarize recent advances in the MSI pathogenesis of GI cancer, with the focus on its relationship with miRNA as well as on the potential to use MSI and related alterations as biomarkers and novel therapeutic targets.展开更多
MicroRNAs （miRNAs） are approximately 22-nucleotide-long non-coding RNAs that are important regulators of gene expression in eukaryotes, miRNAs are first transcribed as long primary transcripts, which then undergo a ...MicroRNAs （miRNAs） are approximately 22-nucleotide-long non-coding RNAs that are important regulators of gene expression in eukaryotes, miRNAs are first transcribed as long primary transcripts, which then undergo a series of processing steps to produce the single-stranded mature miRNAs. This article reviews our current knowledge of the mechanism and regulation of mammalian miRNA expression and points out areas of research that may enhance our understanding of how the specificity and efficiency of miRNA pro- duction is controlled in vivo.展开更多
MicroRNAs（miRNAs）constitute a class of small non-coding RNAs that participate in various biological processes by repressing protein translation or destabilizing target mRNAs.miRNA biogenesis begins with the transcri...MicroRNAs（miRNAs）constitute a class of small non-coding RNAs that participate in various biological processes by repressing protein translation or destabilizing target mRNAs.miRNA biogenesis begins with the transcription of primary miRNAs（pri-miRNAs）in the cell nucleus,which are then cleaved by the Drosha/DGCR complex into precursor miRNAs（pre-miRNAs）.The pre-miRNAs are transported by exportin-5（XPO5）from the nucleus to the cytoplasm,展开更多
Dawdle （DDL） is a microRNA processing protein essential for the development of Arabidopsis. DDL contains a putative nuclear localization signal at its amino-terminus and forkhead-associated （FHA） domain at the car...Dawdle （DDL） is a microRNA processing protein essential for the development of Arabidopsis. DDL contains a putative nuclear localization signal at its amino-terminus and forkhead-associated （FHA） domain at the carboxyl-termi- nus. Here, we report the crystal structure of the FHA domain of Arabidopsis Dawdle, determined by multiple-wavelength anomalous dispersion method at 1.7-A resolution. DDL FHA structure displays a seven-stranded 13-sandwich architec- ture that contains a unique structural motif comprising two long anti-parallel strands. Strikingly, crystal packing of the DDL FHA domain reveals that a glutamate residue from the symmetry-related DDL FHA domain, a structural mimic of the phospho-threonine, is specifically recognized by the structurally conserved phospho-threonine binding cleft. Consistently with the structural observations, co-immuno-precipitation experiments performed in Nicotiana benthami- ana show that the DDL FHA domain co-immuno-precipitates with DCL1 fragments containing the predicted pThr＋3（lle/ Val/Leu/Asp） motif. Taken together, we count the recognition of the target residue by the canonical binding cleft of the DDL FHA domain as the key molecular event to instate FHA domain-mediated protein-protein interaction in plant miRNA processing.展开更多
基金Supported by Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan
文摘There is an increasing understanding of the roles that microsatellite instability （MSI） plays in Lynch syndrome （by mutations） and sporadic （by mainly epigenetic changes） gastrointestinal （GI） and other cancers. Defi- cient DNA mismatch repair （MMR） results in the strong mutator phenotype known as MSI, which is the hall- mark of cancers arising within Lynch syndrome. MSI is characterized by length alterations within simple repeated sequences called microsatellites. Lynch syn- drome occurs primarily because of germline mutations in one of the MMR genes, mainly MLH1 or MSH2, less frequently MSH6, and rarely PMS2. MSI is also observed in about 15% of sporadic colorectal, gastric, and en-dometrial cancers and in lower frequencies in a minor- ity of other cancers where it is often associated with the hypermethylation of the IVlLH1 gene. miRNAs are small noncoding RNAs that regulate gene expression at the posttranscriptional level and are critical in many biological processes and cellular pathways. There is accumulating evidence to support the notion that the interrelationship between MSI and miRNA plays a key role in the pathogenesis of GI cancer. As a possible new mechanism underlying MSI, overexpression of m/R-IEE has been shown to downregulate expression of MLH1, IVlSH2, and MSH6. Thus, a subset of MSI-positive （MSI＋） cancers without known MMR defects may result from m/R-1E5 overexpression. Target genes of frameshift mutation for MSI are involved in various cellular func- tions, such as DNA repair, cell signaling, and apoptosis. A novel class of target genes that included not only epi- genetic modifier genes, such as HDAC2, but also miRNA processing machinery genes, including TARBP2 and XPO5, were found to be mutated in MSI＋ GI cancers. Thus, a subset of MSI＋ colorectal cancers （CRCs） has been proposed to exhibit a mutated miRNA machinery phenotype. Genetic, epigenetic, and transcriptomic dif- ferences exist between MSI＋ and MSI- cancers. Mo- lecular signatures of miRNA expression apparently have the potential to distinguish between MSI＋ and MSI- CRCs. In this review, we summarize recent advances in the MSI pathogenesis of GI cancer, with the focus on its relationship with miRNA as well as on the potential to use MSI and related alterations as biomarkers and novel therapeutic targets.
基金the support of the American Heart Association(Grant No. 0835471N)
文摘MicroRNAs （miRNAs） are approximately 22-nucleotide-long non-coding RNAs that are important regulators of gene expression in eukaryotes, miRNAs are first transcribed as long primary transcripts, which then undergo a series of processing steps to produce the single-stranded mature miRNAs. This article reviews our current knowledge of the mechanism and regulation of mammalian miRNA expression and points out areas of research that may enhance our understanding of how the specificity and efficiency of miRNA pro- duction is controlled in vivo.
文摘MicroRNAs（miRNAs）constitute a class of small non-coding RNAs that participate in various biological processes by repressing protein translation or destabilizing target mRNAs.miRNA biogenesis begins with the transcription of primary miRNAs（pri-miRNAs）in the cell nucleus,which are then cleaved by the Drosha/DGCR complex into precursor miRNAs（pre-miRNAs）.The pre-miRNAs are transported by exportin-5（XPO5）from the nucleus to the cytoplasm,
文摘Dawdle （DDL） is a microRNA processing protein essential for the development of Arabidopsis. DDL contains a putative nuclear localization signal at its amino-terminus and forkhead-associated （FHA） domain at the carboxyl-termi- nus. Here, we report the crystal structure of the FHA domain of Arabidopsis Dawdle, determined by multiple-wavelength anomalous dispersion method at 1.7-A resolution. DDL FHA structure displays a seven-stranded 13-sandwich architec- ture that contains a unique structural motif comprising two long anti-parallel strands. Strikingly, crystal packing of the DDL FHA domain reveals that a glutamate residue from the symmetry-related DDL FHA domain, a structural mimic of the phospho-threonine, is specifically recognized by the structurally conserved phospho-threonine binding cleft. Consistently with the structural observations, co-immuno-precipitation experiments performed in Nicotiana benthami- ana show that the DDL FHA domain co-immuno-precipitates with DCL1 fragments containing the predicted pThr＋3（lle/ Val/Leu/Asp） motif. Taken together, we count the recognition of the target residue by the canonical binding cleft of the DDL FHA domain as the key molecular event to instate FHA domain-mediated protein-protein interaction in plant miRNA processing.
