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      Ubiquitin C-terminal hydrolase isozyme L1 is associated with shelterin complex at interstitial telomeric sites

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          Abstract

          Background

          Ubiquitin C-terminal hydrolase isozyme L1 (UCHL1) is primarily expressed in neuronal cells and neuroendocrine cells and has been associated with various diseases, including many cancers. It is a multifunctional protein involved in deubiquitination, ubiquitination and ubiquitin homeostasis, but its specific roles are disputed and still generally undetermined.

          Results

          Herein, we demonstrate that UCHL1 is associated with genomic DNA in certain prostate cancer cell lines, including DU 145 cells derived from a brain metastatic site, and in HEK293T embryonic kidney cells with a neuronal lineage. Chromatin immunoprecipitation and sequencing revealed that UCHL1 localizes to TTAGGG repeats at telomeres and interstitial telomeric sequences, as do TRF1 and TRF2, components of the shelterin complex. A weak or transient interaction between UCHL1 and the shelterin complex was confirmed by immunoprecipitation and proximity ligation assays. UCHL1 and RAP1, also known as TERF2IP and a component of the shelterin complex, were bound to the nuclear scaffold.

          Conclusions

          We demonstrated a novel feature of UCHL1 in binding telomeres and interstitial telomeric sites.

          Electronic supplementary material

          The online version of this article (10.1186/s13072-017-0160-2) contains supplementary material, which is available to authorized users.

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          Most cited references 58

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          CEAS: cis-regulatory element annotation system.

          We present a tool designed to characterize genome-wide protein-DNA interaction patterns from ChIP-chip and ChIP-Seq data. This stand-alone extension of our web application CEAS (cis-regulatory element annotation system) provides summary statistics on ChIP enrichment in important genomic regions such as individual chromosomes, promoters, gene bodies or exons, and infers the genes most likely to be regulated by the binding factor under study. CEAS also enables biologists to visualize the average ChIP enrichment signals over specific genomic regions, particularly allowing observation of continuous and broad ChIP enrichment that might be too subtle to detect from ChIP peaks alone. The CEAS Python package is publicly available at http://liulab.dfci.harvard.edu/CEAS.
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            Androgen-independent cancer progression and bone metastasis in the LNCaP model of human prostate cancer.

            Our laboratory has previously reported on the derivation of LNCaP cell sublines from LNCaP tumors maintained in castrated and intact athymic male mice. These LNCaP sublines differ from the parental line in tumorigenicity and androgen dependence. This paper demonstrates that one of these sublines acquired metastatic potential. When inoculated either s.c. or orthotopically, the C4-2 subline metastasized to the lymph node and bone with an incidence of 11-50%. Interestingly, the incidence of osseous metastasis was higher in castrated than in intact male hosts. We evaluated the chromosomal, immunohistochemical, and biochemical characteristics of the LNCaP sublines derived from C4-2 tumors that metastasized to the lymph node and bone. Cytogenetic analysis showed that all sublines were human and shared common marker chromosomes with the parental LNCaP cells. This experimental human prostate cancer model may permit, for the first time, the study of the molecular mechanisms underlying human prostate cancer metastasis.
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              The UCH-L1 gene encodes two opposing enzymatic activities that affect alpha-synuclein degradation and Parkinson's disease susceptibility.

              The assumption that each enzyme expresses a single enzymatic activity in vivo is challenged by the linkage of the neuronal enzyme ubiquitin C-terminal hydrolase-L1 (UCH-L1) to Parkinson's disease (PD). UCH-L1, especially those variants linked to higher susceptibility to PD, causes the accumulation of alpha-synuclein in cultured cells, an effect that cannot be explained by its recognized hydrolase activity. UCH-L1 is shown here to exhibit a second, dimerization-dependent, ubiquityl ligase activity. A polymorphic variant of UCH-L1 that is associated with decreased PD risk (S18Y) has reduced ligase activity but comparable hydrolase activity as the wild-type enzyme. Thus, the ligase activity as well as the hydrolase activity of UCH-L1 may play a role in proteasomal protein degradation, a critical process for neuronal health.
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                Author and article information

                Contributors
                alex_ilic@hotmail.com
                SULU@augusta.edu
                charulbhatia@gmail.com
                Farhana.Begum@umanitoba.ca
                Thomas.Klonisch@umanitoba.ca
                PAgarwal@chrim.ca
                Wayne.Xu@umanitoba.ca
                jim.davie@umanitoba.ca
                Journal
                Epigenetics Chromatin
                Epigenetics Chromatin
                Epigenetics & Chromatin
                BioMed Central (London )
                1756-8935
                10 November 2017
                10 November 2017
                2017
                : 10
                Affiliations
                [1 ]ISNI 0000 0004 1936 9609, GRID grid.21613.37, Children’s Hospital Research Institute of Manitoba, , University of Manitoba, ; 715 McDermot Avenue, Room 600A, Winnipeg, MB R3E 3P4 Canada
                [2 ]ISNI 0000 0004 1936 9609, GRID grid.21613.37, Department of Human Anatomy and Cell Science, , University of Manitoba, ; 130-745 Bannatyne Ave, Winnipeg, MB R3E 0J9 Canada
                Article
                160
                10.1186/s13072-017-0160-2
                5681776
                29126443
                © The Author(s) 2017

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/100009326, Cancer Research Society;
                Funded by: FundRef http://dx.doi.org/10.13039/501100000038, Natural Sciences and Engineering Research Council of Canada;
                Funded by: FundRef http://dx.doi.org/10.13039/501100000147, Canadian Breast Cancer Foundation;
                Funded by: FundRef http://dx.doi.org/10.13039/501100000024, Canadian Institutes of Health Research;
                Categories
                Research
                Custom metadata
                © The Author(s) 2017

                Genetics

                shelterin complex, uchl1, interstitial telomeric sites, prostate cancer

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