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  • 1
    Publication Date: 2018-03-06
    Description: Cellular senescence has been viewed as a tumor suppression mechanism and also as a contributor to individual aging. Widespread shortening of 3' untranslated regions (3' UTRs) in messenger RNAs (mRNAs) by alternative polyadenylation (APA) has recently been discovered in cancer cells. However, the role of APA in the process of cellular senescence remains elusive. Here, we found that hundreds of genes in senescent cells tended to use distal poly(A) (pA) sites, leading to a global lengthening of 3' UTRs and reduced gene expression. Genes that harbor longer 3' UTRs in senescent cells were enriched in senescence-related pathways. Rras2 , a member of the Ras superfamily that participates in multiple signal transduction pathways, preferred longer 3' UTR usage and exhibited decreased expression in senescent cells. Depletion of Rras2 promoted senescence, while rescue of Rras2 reversed senescence-associated phenotypes. Mechanistically, splicing factor TRA2B bound to a core "AGAA" motif located in the alternative 3' UTR of Rras2 , thereby reducing the RRAS2 protein level and causing senescence. Both proximal and distal poly(A) signals showed strong sequence conservation, highlighting the vital role of APA regulation during evolution. Our results revealed APA as a novel mechanism in regulating cellular senescence.
    Electronic ISSN: 1549-5469
    Topics: Biology , Medicine
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  • 2
    Publication Date: 2014-05-13
    Description: The global shortening of messenger RNAs through alternative polyadenylation (APA) that occurs during enhanced cellular proliferation represents an important, yet poorly understood mechanism of regulated gene expression. The 3' untranslated region (UTR) truncation of growth-promoting mRNA transcripts that relieves intrinsic microRNA- and AU-rich-element-mediated repression has been observed to correlate with cellular transformation; however, the importance to tumorigenicity of RNA 3'-end-processing factors that potentially govern APA is unknown. Here we identify CFIm25 as a broad repressor of proximal poly(A) site usage that, when depleted, increases cell proliferation. Applying a regression model on standard RNA-sequencing data for novel APA events, we identified at least 1,450 genes with shortened 3' UTRs after CFIm25 knockdown, representing 11% of significantly expressed mRNAs in human cells. Marked increases in the expression of several known oncogenes, including cyclin D1, are observed as a consequence of CFIm25 depletion. Importantly, we identified a subset of CFIm25-regulated APA genes with shortened 3' UTRs in glioblastoma tumours that have reduced CFIm25 expression. Downregulation of CFIm25 expression in glioblastoma cells enhances their tumorigenic properties and increases tumour size, whereas CFIm25 overexpression reduces these properties and inhibits tumour growth. These findings identify a pivotal role of CFIm25 in governing APA and reveal a previously unknown connection between CFIm25 and glioblastoma tumorigenicity.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4128630/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4128630/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Masamha, Chioniso P -- Xia, Zheng -- Yang, Jingxuan -- Albrecht, Todd R -- Li, Min -- Shyu, Ann-Bin -- Li, Wei -- Wagner, Eric J -- CA166274/CA/NCI NIH HHS/ -- CA167752/CA/NCI NIH HHS/ -- GM046454/GM/NIGMS NIH HHS/ -- R01 GM046454/GM/NIGMS NIH HHS/ -- R01 HG007538/HG/NHGRI NIH HHS/ -- R01HG007538/HG/NHGRI NIH HHS/ -- England -- Nature. 2014 Jun 19;510(7505):412-6. doi: 10.1038/nature13261. Epub 2014 May 11.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Department of Biochemistry and Molecular Biology, The University of Texas Medical School at Houston, Houston, Texas 77030, USA [2]. ; 1] Division of Biostatistics, Dan L Duncan Cancer Center and Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, 77030 Texas, USA [2]. ; The Vivian L. Smith Department of Neurosurgery, The University of Texas Medical School at Houston, Houston, Texas 77030, USA. ; Department of Biochemistry and Molecular Biology, The University of Texas Medical School at Houston, Houston, Texas 77030, USA. ; Division of Biostatistics, Dan L Duncan Cancer Center and Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, 77030 Texas, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24814343" target="_blank"〉PubMed〈/a〉
    Keywords: 3' Untranslated Regions ; Animals ; Carcinogenesis/*genetics/metabolism ; Cell Line ; Cell Line, Tumor ; Cell Proliferation ; Gene Expression Profiling ; *Gene Expression Regulation, Neoplastic ; Gene Knockdown Techniques ; Glioblastoma/*physiopathology ; HeLa Cells ; Heterografts ; Humans ; Male ; Mice ; *Polyadenylation ; RNA, Messenger/*metabolism ; Regression Analysis ; mRNA Cleavage and Polyadenylation Factors/*metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 3
    Publication Date: 2018-09-15
    Description: Complex, three-dimensional (3D) mesostructures that incorporate advanced, mechanically active materials are of broad, growing interest for their potential use in many emerging systems. The technology implications range from precision-sensing microelectromechanical systems, to tissue scaffolds that exploit the principles of mechanobiology, to mechanical energy harvesters that support broad bandwidth operation. The work presented here introduces strategies in guided assembly and heterogeneous materials integration as routes to complex, 3D microscale mechanical frameworks that incorporate multiple, independently addressable piezoelectric thin-film actuators for vibratory excitation and precise control. The approach combines transfer printing as a scheme for materials integration with structural buckling as a means for 2D-to-3D geometric transformation, for designs that range from simple, symmetric layouts to complex, hierarchical configurations, on planar or curvilinear surfaces. Systematic experimental and computational studies reveal the underlying characteristics and capabilities, including selective excitation of targeted vibrational modes for simultaneous measurements of viscosity and density of surrounding fluids. The results serve as the foundations for unusual classes of mechanically active 3D mesostructures with unique functions relevant to biosensing, mechanobiology, energy harvesting, and others.
    Electronic ISSN: 2375-2548
    Topics: Natural Sciences in General
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  • 4
    Publication Date: 2014-03-05
    Description: Recognition of modified histones by 'reader' proteins plays a critical role in the regulation of chromatin. H3K36 trimethylation (H3K36me3) is deposited onto the nucleosomes in the transcribed regions after RNA polymerase II elongation. In yeast, this mark in turn recruits epigenetic regulators to reset the chromatin to a relatively repressive state, thus suppressing cryptic transcription. However, much less is known about the role of H3K36me3 in transcription regulation in mammals. This is further complicated by the transcription-coupled incorporation of the histone variant H3.3 in gene bodies. Here we show that the candidate tumour suppressor ZMYND11 specifically recognizes H3K36me3 on H3.3 (H3.3K36me3) and regulates RNA polymerase II elongation. Structural studies show that in addition to the trimethyl-lysine binding by an aromatic cage within the PWWP domain, the H3.3-dependent recognition is mediated by the encapsulation of the H3.3-specific 'Ser 31' residue in a composite pocket formed by the tandem bromo-PWWP domains of ZMYND11. Chromatin immunoprecipitation followed by sequencing shows a genome-wide co-localization of ZMYND11 with H3K36me3 and H3.3 in gene bodies, and its occupancy requires the pre-deposition of H3.3K36me3. Although ZMYND11 is associated with highly expressed genes, it functions as an unconventional transcription co-repressor by modulating RNA polymerase II at the elongation stage. ZMYND11 is critical for the repression of a transcriptional program that is essential for tumour cell growth; low expression levels of ZMYND11 in breast cancer patients correlate with worse prognosis. Consistently, overexpression of ZMYND11 suppresses cancer cell growth in vitro and tumour formation in mice. Together, this study identifies ZMYND11 as an H3.3-specific reader of H3K36me3 that links the histone-variant-mediated transcription elongation control to tumour suppression.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4142212/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4142212/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wen, Hong -- Li, Yuanyuan -- Xi, Yuanxin -- Jiang, Shiming -- Stratton, Sabrina -- Peng, Danni -- Tanaka, Kaori -- Ren, Yongfeng -- Xia, Zheng -- Wu, Jun -- Li, Bing -- Barton, Michelle C -- Li, Wei -- Li, Haitao -- Shi, Xiaobing -- CA016672/CA/NCI NIH HHS/ -- P30 CA016672/CA/NCI NIH HHS/ -- R01 GM090077/GM/NIGMS NIH HHS/ -- R01 HG007538/HG/NHGRI NIH HHS/ -- R01GM090077/GM/NIGMS NIH HHS/ -- R01HG007538/HG/NHGRI NIH HHS/ -- England -- Nature. 2014 Apr 10;508(7495):263-8. doi: 10.1038/nature13045. Epub 2014 Mar 2.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Department of Biochemistry and Molecular Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA [2] Center for Cancer Epigenetics, Center for Genetics and Genomics, and Center for Stem Cell and Developmental Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA [3]. ; 1] MOE Key Laboratory of Protein Sciences, Center for Structural Biology, School of Life Sciences, Tsinghua University, Beijing 100084, China [2] Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing 100084, China [3]. ; 1] Dan L. Duncan Cancer Center, Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA [2]. ; Department of Biochemistry and Molecular Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA. ; 1] MOE Key Laboratory of Protein Sciences, Center for Structural Biology, School of Life Sciences, Tsinghua University, Beijing 100084, China [2] Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing 100084, China. ; Dan L. Duncan Cancer Center, Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA. ; Department of Molecular Biology, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA. ; 1] Department of Biochemistry and Molecular Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA [2] Center for Cancer Epigenetics, Center for Genetics and Genomics, and Center for Stem Cell and Developmental Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA [3] Genes and Development Graduate Program, The University of Texas Graduate School of Biomedical Sciences, Houston, Teaxs 77030, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24590075" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Animals ; Breast Neoplasms/*genetics/metabolism/*pathology ; Carrier Proteins/chemistry/*metabolism ; Chromatin/genetics/metabolism ; Co-Repressor Proteins/chemistry/metabolism ; Crystallography, X-Ray ; Disease-Free Survival ; Female ; Gene Expression Regulation, Neoplastic/genetics ; Histones/chemistry/*metabolism ; Humans ; Lysine/*metabolism ; Methylation ; Mice ; Mice, Nude ; Models, Molecular ; Molecular Sequence Data ; Oncogenes/genetics ; Prognosis ; Protein Binding ; Protein Conformation ; Protein Structure, Tertiary ; RNA Polymerase II/*metabolism ; Substrate Specificity ; *Transcription Elongation, Genetic
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 5
    Publication Date: 2012-02-03
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Xu, Juncai -- Liu, Min -- Xia, Zhijie -- England -- Nature. 2012 Feb 1;482(7383):35. doi: 10.1038/482035d.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22297960" target="_blank"〉PubMed〈/a〉
    Keywords: Humans ; *Medicine, East Asian Traditional
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 6
    Publication Date: 2018-02-23
    Description: Background The mechanism of intramanchette transport is crucial to the transformation of sperm tail and the nuclear condensation during spermiogenesis. Although few dysfunctional proteins could result in abnormal junction between the head and tail of spermatozoon, little is known about the genetic cues in this process. Objective Based on patients with severe decapitated and decaudated spermatozoa (DDS) syndrome, the study aimed to validate whether new mutation exists on their Hook microtubule-tethering protein 1 ( HOOK1 ) genes and follow their results of assisted reproduction treatment (ART). Methods 7 severe teratozoospermia patients with DDS (proportion 〉95%) and three relative members in one pedigree were collected to sequence the whole genomic DNA. The fertilisation rates (FRs) of these patients were followed. Morphological observation and interspecies intracytoplasmic sperm injection (ICSI) assays were applied. Results A novel missense mutation of A to G (p.Q286R) in patients with DDS (n=3/7) was found in the HOOK1 gene, which was inherited from the mother in one patient. This variant was absent in 160 fertile population-matched control individuals. Morphological observation showed that almost all the DDS broke into decaudated heads and headless tails at the implantation fossa or the basal plate. The clinical studies indicated that the mutation might cause reduced FRs on both ART (FR=18.07%) and interspecies ICSI (FR=16.98%). Conclusions An unreported mutation in HOOK1 gene was identified, which might be responsible to some patients with DDS. Further studies need to uncover the molecular mechanism of spermiogenesis for genomic therapy.
    Print ISSN: 0022-2593
    Electronic ISSN: 1468-6244
    Topics: Medicine
    Published by BMJ Publishing Group
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  • 7
    ISSN: 0168-583X
    Source: Elsevier Journal Backfiles on ScienceDirect 1907 - 2002
    Topics: Physics
    Type of Medium: Electronic Resource
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  • 8
    ISSN: 0169-4332
    Source: Elsevier Journal Backfiles on ScienceDirect 1907 - 2002
    Topics: Physics
    Type of Medium: Electronic Resource
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  • 9
    Electronic Resource
    Electronic Resource
    Amsterdam : Elsevier
    Surface & Coatings Technology 48 (1991), S. 237-239 
    ISSN: 0257-8972
    Source: Elsevier Journal Backfiles on ScienceDirect 1907 - 2002
    Topics: Mechanical Engineering, Materials Science, Production Engineering, Mining and Metallurgy, Traffic Engineering, Precision Mechanics , Physics
    Type of Medium: Electronic Resource
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  • 10
    ISSN: 0888-7543
    Source: Elsevier Journal Backfiles on ScienceDirect 1907 - 2002
    Topics: Biology , Medicine
    Type of Medium: Electronic Resource
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