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      Pwp1 regulates telomere length by stabilizing shelterin complex and maintaining histone H4K20 trimethylation

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          Abstract

          Telomere maintenance is critical for chromosome stability. Here we report that periodic tryptophan protein 1 (PWP1) is involved in regulating telomere length homeostasis. Pwp1 appears to be essential for mouse development and embryonic stem cell (ESC) survival, as homozygous Pwp1-knockout mice and ESCs have never been obtained. Heterozygous Pwp1-knockout mice had shorter telomeres and decreased reproductive capacity. Pwp1 depletion induced rapid telomere shortening accompanied by reduced shelterin complex and increased DNA damage in telomeric regions. Mechanistically, PWP1 bound and stabilized the shelterin complex via its WD40 domains and regulated the overall level of H4K20me3. The rescue of telomere length in Pwp1-deficient cells by PWP1 overexpression depended on SUV4-20H2 co-expression and increased H4K20me3. Therefore, our study revealed a novel protein involved in telomere homeostasis in both mouse and human cells. This knowledge will improve our understanding of how chromatin structure and histone modifications are involved in maintaining telomere integrity.

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          Most cited references50

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          Telomeres and human disease: ageing, cancer and beyond.

          Telomere length and telomerase activity are important factors in the pathobiology of human disease. Age-related diseases and premature ageing syndromes are characterized by short telomeres, which can compromise cell viability, whereas tumour cells can prevent telomere loss by aberrantly upregulating telomerase. Altered functioning of both telomerase and telomere-interacting proteins is present in some human premature ageing syndromes and in cancer, and recent findings indicate that alterations that affect telomeres at the level of chromatin structure might also have a role in human disease. These findings have inspired a number of potential therapeutic strategies that are based on telomerase and telomeres.
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            WD40 proteins propel cellular networks.

            Recent findings indicate that WD40 domains play central roles in biological processes by acting as hubs in cellular networks; however, they have been studied less intensely than other common domains, such as the kinase, PDZ or SH3 domains. As suggested by various interactome studies, they are among the most promiscuous interactors. Structural studies suggest that this property stems from their ability, as scaffolds, to interact with diverse proteins, peptides or nucleic acids using multiple surfaces or modes of interaction. A general scaffolding role is supported by the fact that no WD40 domain has been found with intrinsic enzymatic activity despite often being part of large molecular machines. We discuss the WD40 domain distributions in protein networks and structures of WD40-containing assemblies to demonstrate their versatility in mediating critical cellular functions. Copyright © 2010 Elsevier Ltd. All rights reserved.
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              TERRA RNA binding to TRF2 facilitates heterochromatin formation and ORC recruitment at telomeres.

              Telomere-repeat-encoding RNA (referred to as TERRA) has been identified as a potential component of yeast and mammalian telomeres. We show here that TERRA RNA interacts with several telomere-associated proteins, including telomere repeat factors 1 (TRF1) and 2 (TRF2), subunits of the origin recognition complex (ORC), heterochromatin protein 1 (HP1), histone H3 trimethyl K9 (H3 K9me3), and members of the DNA-damage-sensing pathway. siRNA depletion of TERRA caused an increase in telomere dysfunction-induced foci, aberrations in metaphase telomeres, and a loss of histone H3 K9me3 and ORC at telomere repeat DNA. Previous studies found that TRF2 amino-terminal GAR domain recruited ORC to telomeres. We now show that TERRA RNA can interact directly with the TRF2 GAR and ORC1 to form a stable ternary complex. We conclude that TERRA facilitates TRF2 interaction with ORC and plays a central role in telomere structural maintenance and heterochromatin formation.
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                Author and article information

                Contributors
                wuj3@tongji.edu.cn
                jiyue.zhu@wsu.edu
                jhkang@tongji.edu.cn
                Journal
                Cell Discov
                Cell Discov
                Cell Discovery
                Nature Publishing Group UK (London )
                2056-5968
                5 November 2019
                5 November 2019
                2019
                : 5
                : 47
                Affiliations
                [1 ]ISNI 0000000123704535, GRID grid.24516.34, Clinical and Translational Research Center of Shanghai First Maternity and Infant Hospital, Shanghai Key Laboratory of Signaling and Disease Research, Collaborative Innovation Center for Brain Science; School of Life Sciences and Technology, , Tongji University, ; Shanghai, 200092 China
                [2 ]ISNI 0000000123704535, GRID grid.24516.34, Institute for Regenerative Medicine, Shanghai East Hospital, School of Life Sciences and Technology, , Tongji University, ; Shanghai, 200123 China
                [3 ]ISNI 0000000123704535, GRID grid.24516.34, Department of Gynecology, Shanghai First Maternity and Infant Hospital, School of Medicine, , Tongji University, ; Shanghai, 201204 P. R. China
                [4 ]ISNI 0000 0001 2157 6568, GRID grid.30064.31, Department of Pharmaceutical Sciences, College of Pharmacy, , Washington State University, ; Spokane, WA 99210 USA
                Author information
                http://orcid.org/0000-0003-1041-3928
                Article
                116
                10.1038/s41421-019-0116-8
                6868014
                31754456
                6cc67dc6-5c8a-42d5-9ff4-c2a41f3307c0
                © The Author(s) 2019

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as 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 images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 10 December 2018
                : 24 July 2019
                Funding
                Funded by: The Major Program of Development Fund for Shanghai Zhangjiang National Innovation Demonstration Zone (ZJ2018-ZD-004);The Ministry of Science and Technology (2016YFA0101300); National Natural Science Foundation of China (31671533, 81530042, 31571529, 31721003,31771506); National Institutes of Health grant R01GM071725, Shanghai municipal medical and health discipline construction project (2017ZZ02015) and the Fundamental Research Funds for the Central Universities (KX0151520172571).
                Funded by: †he Major Program of Development Fund for Shanghai Zhangjiang National Innovation Demonstration Zone (ZJ2018-ZD-004);The Ministry of Science and Technology (2016YFA0101300); National Natural Science Foundation of China (31671533, 81530042, 31571529, 31721003,31771506); National Institutes of Health grant R01GM071725, Shanghai municipal medical and health discipline construction project (2017ZZ02015) and the Fundamental Research Funds for the Central Universities (KX0151520172571).
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                © The Author(s) 2019

                telomeres,embryonic stem cells
                telomeres, embryonic stem cells

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