Telomere Replication Stress Induced by POT1 Inactivation Accelerates Tumorigenesis
Genome sequencing studies have revealed a number of cancer-associated mutations in the telomere-binding factor POT1. Here, we show that when combined with p53 deficiency, depletion of murine POT1a in common lymphoid progenitor cells fosters genetic instability, accelerates the onset, and increases t...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2016-06-01
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| Series: | Cell Reports |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124716305617 |
| _version_ | 1819212695487905792 |
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| author | Alexandra M. Pinzaru Robert A. Hom Angela Beal Aaron F. Phillips Eric Ni Timothy Cardozo Nidhi Nair Jaehyuk Choi Deborah S. Wuttke Agnel Sfeir Eros Lazzerini Denchi |
| author_facet | Alexandra M. Pinzaru Robert A. Hom Angela Beal Aaron F. Phillips Eric Ni Timothy Cardozo Nidhi Nair Jaehyuk Choi Deborah S. Wuttke Agnel Sfeir Eros Lazzerini Denchi |
| author_sort | Alexandra M. Pinzaru |
| collection | DOAJ |
| description | Genome sequencing studies have revealed a number of cancer-associated mutations in the telomere-binding factor POT1. Here, we show that when combined with p53 deficiency, depletion of murine POT1a in common lymphoid progenitor cells fosters genetic instability, accelerates the onset, and increases the severity of T cell lymphomas. In parallel, we examined human and mouse cells carrying POT1 mutations found in cutaneous T cell lymphoma (CTCL) patients. Inhibition of POT1 activates ATR-dependent DNA damage signaling and induces telomere fragility, replication fork stalling, and telomere elongation. Our data suggest that these phenotypes are linked to impaired CST (CTC1-STN1-TEN1) function at telomeres. Lastly, we show that proliferation of cancer cells lacking POT1 is enabled by the attenuation of the ATR kinase pathway. These results uncover a role for defective telomere replication during tumorigenesis. |
| first_indexed | 2024-12-23T06:47:03Z |
| format | Article |
| id | doaj.art-41a03a414ad34762bf0a0a0270c0b8f8 |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-12-23T06:47:03Z |
| publishDate | 2016-06-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-41a03a414ad34762bf0a0a0270c0b8f82022-12-21T17:56:32ZengElsevierCell Reports2211-12472016-06-0115102170218410.1016/j.celrep.2016.05.008Telomere Replication Stress Induced by POT1 Inactivation Accelerates TumorigenesisAlexandra M. Pinzaru0Robert A. Hom1Angela Beal2Aaron F. Phillips3Eric Ni4Timothy Cardozo5Nidhi Nair6Jaehyuk Choi7Deborah S. Wuttke8Agnel Sfeir9Eros Lazzerini Denchi10Department of Cell Biology, Skirball Institute of Biomolecular Medicine, NYU School of Medicine, New York, NY 10016, USADepartment of Chemistry and Biochemistry, University of Colorado, Boulder, CO 80309, USADepartment of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA 92037, USADepartment of Cell Biology, Skirball Institute of Biomolecular Medicine, NYU School of Medicine, New York, NY 10016, USADepartment of Biochemistry and Molecular Pharmacology, NYU School of Medicine, New York, NY 10016, USADepartment of Biochemistry and Molecular Pharmacology, NYU School of Medicine, New York, NY 10016, USADepartment of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA 92037, USADepartments of Dermatology and Biochemistry and Molecular Genetics, Northwestern University, Feinberg School of Medicine, Chicago, IL 60611, USADepartment of Chemistry and Biochemistry, University of Colorado, Boulder, CO 80309, USADepartment of Cell Biology, Skirball Institute of Biomolecular Medicine, NYU School of Medicine, New York, NY 10016, USADepartment of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA 92037, USAGenome sequencing studies have revealed a number of cancer-associated mutations in the telomere-binding factor POT1. Here, we show that when combined with p53 deficiency, depletion of murine POT1a in common lymphoid progenitor cells fosters genetic instability, accelerates the onset, and increases the severity of T cell lymphomas. In parallel, we examined human and mouse cells carrying POT1 mutations found in cutaneous T cell lymphoma (CTCL) patients. Inhibition of POT1 activates ATR-dependent DNA damage signaling and induces telomere fragility, replication fork stalling, and telomere elongation. Our data suggest that these phenotypes are linked to impaired CST (CTC1-STN1-TEN1) function at telomeres. Lastly, we show that proliferation of cancer cells lacking POT1 is enabled by the attenuation of the ATR kinase pathway. These results uncover a role for defective telomere replication during tumorigenesis.http://www.sciencedirect.com/science/article/pii/S2211124716305617POT1telomereATRreplication stressthymic lymphomacutaneous T cell lymphoma |
| spellingShingle | Alexandra M. Pinzaru Robert A. Hom Angela Beal Aaron F. Phillips Eric Ni Timothy Cardozo Nidhi Nair Jaehyuk Choi Deborah S. Wuttke Agnel Sfeir Eros Lazzerini Denchi Telomere Replication Stress Induced by POT1 Inactivation Accelerates Tumorigenesis Cell Reports POT1 telomere ATR replication stress thymic lymphoma cutaneous T cell lymphoma |
| title | Telomere Replication Stress Induced by POT1 Inactivation Accelerates Tumorigenesis |
| title_full | Telomere Replication Stress Induced by POT1 Inactivation Accelerates Tumorigenesis |
| title_fullStr | Telomere Replication Stress Induced by POT1 Inactivation Accelerates Tumorigenesis |
| title_full_unstemmed | Telomere Replication Stress Induced by POT1 Inactivation Accelerates Tumorigenesis |
| title_short | Telomere Replication Stress Induced by POT1 Inactivation Accelerates Tumorigenesis |
| title_sort | telomere replication stress induced by pot1 inactivation accelerates tumorigenesis |
| topic | POT1 telomere ATR replication stress thymic lymphoma cutaneous T cell lymphoma |
| url | http://www.sciencedirect.com/science/article/pii/S2211124716305617 |
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