--- _id: '12051' abstract: - lang: eng text: Transcription of the ribosomal RNA precursor by RNA polymerase (Pol) I is a major determinant of cellular growth, and dysregulation is observed in many cancer types. Here, we present the purification of human Pol I from cells carrying a genomic GFP fusion on the largest subunit allowing the structural and functional analysis of the enzyme across species. In contrast to yeast, human Pol I carries a single-subunit stalk, and in vitro transcription indicates a reduced proofreading activity. Determination of the human Pol I cryo-EM reconstruction in a close-to-native state rationalizes the effects of disease-associated mutations and uncovers an additional domain that is built into the sequence of Pol I subunit RPA1. This “dock II” domain resembles a truncated HMG box incapable of DNA binding which may serve as a downstream transcription factor–binding platform in metazoans. Biochemical analysis, in situ modelling, and ChIP data indicate that Topoisomerase 2a can be recruited to Pol I via the domain and cooperates with the HMG box domain–containing factor UBF. These adaptations of the metazoan Pol I transcription system may allow efficient release of positive DNA supercoils accumulating downstream of the transcription bubble. acknowledgement: "The authors especially thank Philip Gunkel for his contribution. We thank all\r\npast and present members of the Engel lab, Achim Griesenbeck, Colyn Crane-\r\nRobinson, Christophe Lotz, Marlene Vayssieres, Klaus Grasser, Herbert Tschochner, and Philipp Milkereit for help and discussion; Gerhard Lehmann and Nobert Eichner for IT support; Joost Zomerdijk for UBF-constructs, Volker Cordes for the Hela P2 cell line; Remco Sprangers for shared cell culture; Dina Grohmann and the Archaea Center for fermentation; and Thomas\r\nDresselhaus for access to fluorescence microscopes. This work was in part supported by the Emmy-Noether Programm (DFG grant no. EN 1204/1-1 to C Engel) of the German Research Council and Collaborative Research Center 960 (TP-A8 to C Engel)." article_number: e202201568 article_processing_charge: No article_type: original author: - first_name: Julia L full_name: Daiß, Julia L last_name: Daiß - first_name: Michael full_name: Pilsl, Michael last_name: Pilsl - first_name: Kristina full_name: Straub, Kristina last_name: Straub - first_name: Andrea full_name: Bleckmann, Andrea last_name: Bleckmann - first_name: Mona full_name: Höcherl, Mona last_name: Höcherl - first_name: Florian B full_name: Heiss, Florian B last_name: Heiss - first_name: Guillermo full_name: Abascal-Palacios, Guillermo last_name: Abascal-Palacios - first_name: Ewan P full_name: Ramsay, Ewan P last_name: Ramsay - first_name: Katarina full_name: Tluckova, Katarina id: 4AC7D980-F248-11E8-B48F-1D18A9856A87 last_name: Tluckova - first_name: Jean-Clement full_name: Mars, Jean-Clement last_name: Mars - first_name: Torben full_name: Fürtges, Torben last_name: Fürtges - first_name: Astrid full_name: Bruckmann, Astrid last_name: Bruckmann - first_name: Till full_name: Rudack, Till last_name: Rudack - first_name: Carrie A full_name: Bernecky, Carrie A id: 2CB9DFE2-F248-11E8-B48F-1D18A9856A87 last_name: Bernecky orcid: 0000-0003-0893-7036 - first_name: Valérie full_name: Lamour, Valérie last_name: Lamour - first_name: Konstantin full_name: Panov, Konstantin last_name: Panov - first_name: Alessandro full_name: Vannini, Alessandro last_name: Vannini - first_name: Tom full_name: Moss, Tom last_name: Moss - first_name: Christoph full_name: Engel, Christoph last_name: Engel citation: ama: Daiß JL, Pilsl M, Straub K, et al. The human RNA polymerase I structure reveals an HMG-like docking domain specific to metazoans. Life Science Alliance. 2022;5(11). doi:10.26508/lsa.202201568 apa: Daiß, J. L., Pilsl, M., Straub, K., Bleckmann, A., Höcherl, M., Heiss, F. B., … Engel, C. (2022). The human RNA polymerase I structure reveals an HMG-like docking domain specific to metazoans. Life Science Alliance. Life Science Alliance. https://doi.org/10.26508/lsa.202201568 chicago: Daiß, Julia L, Michael Pilsl, Kristina Straub, Andrea Bleckmann, Mona Höcherl, Florian B Heiss, Guillermo Abascal-Palacios, et al. “The Human RNA Polymerase I Structure Reveals an HMG-like Docking Domain Specific to Metazoans.” Life Science Alliance. Life Science Alliance, 2022. https://doi.org/10.26508/lsa.202201568. ieee: J. L. Daiß et al., “The human RNA polymerase I structure reveals an HMG-like docking domain specific to metazoans,” Life Science Alliance, vol. 5, no. 11. Life Science Alliance, 2022. ista: Daiß JL, Pilsl M, Straub K, Bleckmann A, Höcherl M, Heiss FB, Abascal-Palacios G, Ramsay EP, Tluckova K, Mars J-C, Fürtges T, Bruckmann A, Rudack T, Bernecky C, Lamour V, Panov K, Vannini A, Moss T, Engel C. 2022. The human RNA polymerase I structure reveals an HMG-like docking domain specific to metazoans. Life Science Alliance. 5(11), e202201568. mla: Daiß, Julia L., et al. “The Human RNA Polymerase I Structure Reveals an HMG-like Docking Domain Specific to Metazoans.” Life Science Alliance, vol. 5, no. 11, e202201568, Life Science Alliance, 2022, doi:10.26508/lsa.202201568. short: J.L. Daiß, M. Pilsl, K. Straub, A. Bleckmann, M. Höcherl, F.B. Heiss, G. Abascal-Palacios, E.P. Ramsay, K. Tluckova, J.-C. Mars, T. Fürtges, A. Bruckmann, T. Rudack, C. Bernecky, V. Lamour, K. Panov, A. Vannini, T. Moss, C. Engel, Life Science Alliance 5 (2022). date_created: 2022-09-06T18:45:23Z date_published: 2022-09-01T00:00:00Z date_updated: 2023-08-03T13:39:36Z day: '01' ddc: - '570' department: - _id: CaBe doi: 10.26508/lsa.202201568 external_id: isi: - '000972702600001' file: - access_level: open_access checksum: 4201d876a3e5e8b65e319d03300014ad content_type: application/pdf creator: dernst date_created: 2022-09-08T06:41:14Z date_updated: 2022-09-08T06:41:14Z file_id: '12062' file_name: 2022_LifeScienceAlliance_Daiss.pdf file_size: 3183129 relation: main_file success: 1 file_date_updated: 2022-09-08T06:41:14Z has_accepted_license: '1' intvolume: ' 5' isi: 1 issue: '11' keyword: - Health - Toxicology and Mutagenesis - Plant Science - Biochemistry - Genetics and Molecular Biology (miscellaneous) - Ecology language: - iso: eng month: '09' oa: 1 oa_version: Published Version publication: Life Science Alliance publication_identifier: issn: - 2575-1077 publication_status: published publisher: Life Science Alliance quality_controlled: '1' status: public title: The human RNA polymerase I structure reveals an HMG-like docking domain specific to metazoans tmp: image: /images/cc_by.png legal_code_url: https://creativecommons.org/licenses/by/4.0/legalcode name: Creative Commons Attribution 4.0 International Public License (CC-BY 4.0) short: CC BY (4.0) type: journal_article user_id: 4359f0d1-fa6c-11eb-b949-802e58b17ae8 volume: 5 year: '2022' ... --- _id: '11058' abstract: - lang: eng text: Nucleoporin 93 (Nup93) expression inversely correlates with the survival of triple-negative breast cancer patients. However, our knowledge of Nup93 function in breast cancer besides its role as structural component of the nuclear pore complex is not understood. Combination of functional assays and genetic analyses suggested that chromatin interaction of Nup93 partially modulates the expression of genes associated with actin cytoskeleton remodeling and epithelial to mesenchymal transition, resulting in impaired invasion of triple-negative, claudin-low breast cancer cells. Nup93 depletion induced stress fiber formation associated with reduced cell migration/proliferation and impaired expression of mesenchymal-like genes. Silencing LIMCH1, a gene responsible for actin cytoskeleton remodeling and up-regulated upon Nup93 depletion, partially restored the invasive phenotype of cancer cells. Loss of Nup93 led to significant defects in tumor establishment/propagation in vivo, whereas patient samples revealed that high Nup93 and low LIMCH1 expression correlate with late tumor stage. Our approach identified Nup93 as contributor of triple-negative, claudin-low breast cancer cell invasion and paves the way to study the role of nuclear envelope proteins during breast cancer tumorigenesis. article_number: e201900623 article_processing_charge: No article_type: original author: - first_name: Simone full_name: Bersini, Simone last_name: Bersini - first_name: Nikki K full_name: Lytle, Nikki K last_name: Lytle - first_name: Roberta full_name: Schulte, Roberta last_name: Schulte - first_name: Ling full_name: Huang, Ling last_name: Huang - first_name: Geoffrey M full_name: Wahl, Geoffrey M last_name: Wahl - first_name: Martin W full_name: HETZER, Martin W id: 86c0d31b-b4eb-11ec-ac5a-eae7b2e135ed last_name: HETZER orcid: 0000-0002-2111-992X citation: ama: Bersini S, Lytle NK, Schulte R, Huang L, Wahl GM, Hetzer M. Nup93 regulates breast tumor growth by modulating cell proliferation and actin cytoskeleton remodeling. Life Science Alliance. 2020;3(1). doi:10.26508/lsa.201900623 apa: Bersini, S., Lytle, N. K., Schulte, R., Huang, L., Wahl, G. M., & Hetzer, M. (2020). Nup93 regulates breast tumor growth by modulating cell proliferation and actin cytoskeleton remodeling. Life Science Alliance. Life Science Alliance. https://doi.org/10.26508/lsa.201900623 chicago: Bersini, Simone, Nikki K Lytle, Roberta Schulte, Ling Huang, Geoffrey M Wahl, and Martin Hetzer. “Nup93 Regulates Breast Tumor Growth by Modulating Cell Proliferation and Actin Cytoskeleton Remodeling.” Life Science Alliance. Life Science Alliance, 2020. https://doi.org/10.26508/lsa.201900623. ieee: S. Bersini, N. K. Lytle, R. Schulte, L. Huang, G. M. Wahl, and M. Hetzer, “Nup93 regulates breast tumor growth by modulating cell proliferation and actin cytoskeleton remodeling,” Life Science Alliance, vol. 3, no. 1. Life Science Alliance, 2020. ista: Bersini S, Lytle NK, Schulte R, Huang L, Wahl GM, Hetzer M. 2020. Nup93 regulates breast tumor growth by modulating cell proliferation and actin cytoskeleton remodeling. Life Science Alliance. 3(1), e201900623. mla: Bersini, Simone, et al. “Nup93 Regulates Breast Tumor Growth by Modulating Cell Proliferation and Actin Cytoskeleton Remodeling.” Life Science Alliance, vol. 3, no. 1, e201900623, Life Science Alliance, 2020, doi:10.26508/lsa.201900623. short: S. Bersini, N.K. Lytle, R. Schulte, L. Huang, G.M. Wahl, M. Hetzer, Life Science Alliance 3 (2020). date_created: 2022-04-07T07:44:18Z date_published: 2020-01-01T00:00:00Z date_updated: 2022-07-18T08:31:20Z day: '01' ddc: - '570' doi: 10.26508/lsa.201900623 extern: '1' external_id: pmid: - '31959624' file: - access_level: open_access checksum: 3bf33e7e93bef7823287807206b69b38 content_type: application/pdf creator: dernst date_created: 2022-04-08T07:33:01Z date_updated: 2022-04-08T07:33:01Z file_id: '11137' file_name: 2020_LifeScienceAlliance_Bersini.pdf file_size: 2653960 relation: main_file success: 1 file_date_updated: 2022-04-08T07:33:01Z has_accepted_license: '1' intvolume: ' 3' issue: '1' keyword: - Health - Toxicology and Mutagenesis - Plant Science - Biochemistry - Genetics and Molecular Biology (miscellaneous) - Ecology language: - iso: eng month: '01' oa: 1 oa_version: Published Version pmid: 1 publication: Life Science Alliance publication_identifier: issn: - 2575-1077 publication_status: published publisher: Life Science Alliance quality_controlled: '1' scopus_import: '1' status: public title: Nup93 regulates breast tumor growth by modulating cell proliferation and actin cytoskeleton remodeling tmp: image: /images/cc_by.png legal_code_url: https://creativecommons.org/licenses/by/4.0/legalcode name: Creative Commons Attribution 4.0 International Public License (CC-BY 4.0) short: CC BY (4.0) type: journal_article user_id: 72615eeb-f1f3-11ec-aa25-d4573ddc34fd volume: 3 year: '2020' ... --- _id: '8592' abstract: - lang: eng text: Glioblastoma is the most malignant cancer in the brain and currently incurable. It is urgent to identify effective targets for this lethal disease. Inhibition of such targets should suppress the growth of cancer cells and, ideally also precancerous cells for early prevention, but minimally affect their normal counterparts. Using genetic mouse models with neural stem cells (NSCs) or oligodendrocyte precursor cells (OPCs) as the cells‐of‐origin/mutation, it is shown that the susceptibility of cells within the development hierarchy of glioma to the knockout of insulin‐like growth factor I receptor (IGF1R) is determined not only by their oncogenic states, but also by their cell identities/states. Knockout of IGF1R selectively disrupts the growth of mutant and transformed, but not normal OPCs, or NSCs. The desirable outcome of IGF1R knockout on cell growth requires the mutant cells to commit to the OPC identity regardless of its development hierarchical status. At the molecular level, oncogenic mutations reprogram the cellular network of OPCs and force them to depend more on IGF1R for their growth. A new‐generation brain‐penetrable, orally available IGF1R inhibitor harnessing tumor OPCs in the brain is also developed. The findings reveal the cellular window of IGF1R targeting and establish IGF1R as an effective target for the prevention and treatment of glioblastoma. acknowledgement: The authors thank Drs. J. Eisen, QR. Lu, S. Duan, Z‐H. Li, W. Mo, and Q. Wu for their critical comments on the manuscript. They also thank Dr. H. Zong for providing the CKO_NG2‐CreER model. This work is supported by the National Key Research and Development Program of China, Stem Cell and Translational Research (2016YFA0101201 to C.L., 2016YFA0100303 to Y.J.W.), the National Natural Science Foundation of China (81673035 and 81972915 to C.L., 81472722 to Y.J.W.), the Science Foundation for Distinguished Young Scientists of Zhejiang Province (LR17H160001 to C.L.), Fundamental Research Funds for the Central Universities (2016QNA7023 and 2017QNA7028 to C.L.) and the Thousand Talent Program for Young Outstanding Scientists, China (to C.L.), IST Austria institutional funds (to S.H.), European Research Council (ERC) under the European Union's Horizon 2020 research and innovation programme (725780 LinPro to S.H.). C.L. is a scholar of K. C. Wong Education Foundation. article_number: '2001724' article_processing_charge: No article_type: original author: - first_name: Anhao full_name: Tian, Anhao last_name: Tian - first_name: Bo full_name: Kang, Bo last_name: Kang - first_name: Baizhou full_name: Li, Baizhou last_name: Li - first_name: Biying full_name: Qiu, Biying last_name: Qiu - first_name: Wenhong full_name: Jiang, Wenhong last_name: Jiang - first_name: Fangjie full_name: Shao, Fangjie last_name: Shao - first_name: Qingqing full_name: Gao, Qingqing last_name: Gao - first_name: Rui full_name: Liu, Rui last_name: Liu - first_name: Chengwei full_name: Cai, Chengwei last_name: Cai - first_name: Rui full_name: Jing, Rui last_name: Jing - first_name: Wei full_name: Wang, Wei last_name: Wang - first_name: Pengxiang full_name: Chen, Pengxiang last_name: Chen - first_name: Qinghui full_name: Liang, Qinghui last_name: Liang - first_name: Lili full_name: Bao, Lili last_name: Bao - first_name: Jianghong full_name: Man, Jianghong last_name: Man - first_name: Yan full_name: Wang, Yan last_name: Wang - first_name: Yu full_name: Shi, Yu last_name: Shi - first_name: Jin full_name: Li, Jin last_name: Li - first_name: Minmin full_name: Yang, Minmin last_name: Yang - first_name: Lisha full_name: Wang, Lisha last_name: Wang - first_name: Jianmin full_name: Zhang, Jianmin last_name: Zhang - first_name: Simon full_name: Hippenmeyer, Simon id: 37B36620-F248-11E8-B48F-1D18A9856A87 last_name: Hippenmeyer orcid: 0000-0003-2279-1061 - first_name: Junming full_name: Zhu, Junming last_name: Zhu - first_name: Xiuwu full_name: Bian, Xiuwu last_name: Bian - first_name: Ying‐Jie full_name: Wang, Ying‐Jie last_name: Wang - first_name: Chong full_name: Liu, Chong last_name: Liu citation: ama: Tian A, Kang B, Li B, et al. Oncogenic state and cell identity combinatorially dictate the susceptibility of cells within glioma development hierarchy to IGF1R targeting. Advanced Science. 2020;7(21). doi:10.1002/advs.202001724 apa: Tian, A., Kang, B., Li, B., Qiu, B., Jiang, W., Shao, F., … Liu, C. (2020). Oncogenic state and cell identity combinatorially dictate the susceptibility of cells within glioma development hierarchy to IGF1R targeting. Advanced Science. Wiley. https://doi.org/10.1002/advs.202001724 chicago: Tian, Anhao, Bo Kang, Baizhou Li, Biying Qiu, Wenhong Jiang, Fangjie Shao, Qingqing Gao, et al. “Oncogenic State and Cell Identity Combinatorially Dictate the Susceptibility of Cells within Glioma Development Hierarchy to IGF1R Targeting.” Advanced Science. Wiley, 2020. https://doi.org/10.1002/advs.202001724. ieee: A. Tian et al., “Oncogenic state and cell identity combinatorially dictate the susceptibility of cells within glioma development hierarchy to IGF1R targeting,” Advanced Science, vol. 7, no. 21. Wiley, 2020. ista: Tian A, Kang B, Li B, Qiu B, Jiang W, Shao F, Gao Q, Liu R, Cai C, Jing R, Wang W, Chen P, Liang Q, Bao L, Man J, Wang Y, Shi Y, Li J, Yang M, Wang L, Zhang J, Hippenmeyer S, Zhu J, Bian X, Wang Y, Liu C. 2020. Oncogenic state and cell identity combinatorially dictate the susceptibility of cells within glioma development hierarchy to IGF1R targeting. Advanced Science. 7(21), 2001724. mla: Tian, Anhao, et al. “Oncogenic State and Cell Identity Combinatorially Dictate the Susceptibility of Cells within Glioma Development Hierarchy to IGF1R Targeting.” Advanced Science, vol. 7, no. 21, 2001724, Wiley, 2020, doi:10.1002/advs.202001724. short: A. Tian, B. Kang, B. Li, B. Qiu, W. Jiang, F. Shao, Q. Gao, R. Liu, C. Cai, R. Jing, W. Wang, P. Chen, Q. Liang, L. Bao, J. Man, Y. Wang, Y. Shi, J. Li, M. Yang, L. Wang, J. Zhang, S. Hippenmeyer, J. Zhu, X. Bian, Y. Wang, C. Liu, Advanced Science 7 (2020). date_created: 2020-10-01T09:44:13Z date_published: 2020-11-04T00:00:00Z date_updated: 2023-08-22T09:53:01Z day: '04' ddc: - '570' department: - _id: SiHi doi: 10.1002/advs.202001724 ec_funded: 1 external_id: isi: - '000573860700001' file: - access_level: open_access checksum: 92818c23ecc70e35acfa671f3cfb9909 content_type: application/pdf creator: dernst date_created: 2020-12-10T14:07:24Z date_updated: 2020-12-10T14:07:24Z file_id: '8938' file_name: 2020_AdvScience_Tian.pdf file_size: 7835833 relation: main_file success: 1 file_date_updated: 2020-12-10T14:07:24Z has_accepted_license: '1' intvolume: ' 7' isi: 1 issue: '21' keyword: - General Engineering - General Physics and Astronomy - General Materials Science - Medicine (miscellaneous) - General Chemical Engineering - Biochemistry - Genetics and Molecular Biology (miscellaneous) language: - iso: eng month: '11' oa: 1 oa_version: Published Version project: - _id: 260018B0-B435-11E9-9278-68D0E5697425 call_identifier: H2020 grant_number: '725780' name: Principles of Neural Stem Cell Lineage Progression in Cerebral Cortex Development publication: Advanced Science publication_identifier: issn: - 2198-3844 publication_status: published publisher: Wiley quality_controlled: '1' status: public title: Oncogenic state and cell identity combinatorially dictate the susceptibility of cells within glioma development hierarchy to IGF1R targeting tmp: image: /images/cc_by.png legal_code_url: https://creativecommons.org/licenses/by/4.0/legalcode name: Creative Commons Attribution 4.0 International Public License (CC-BY 4.0) short: CC BY (4.0) type: journal_article user_id: 4359f0d1-fa6c-11eb-b949-802e58b17ae8 volume: 7 year: '2020' ...