title: Telomere Replication Stress Induced by POT1 Inactivation Accelerates Tumorigenesis.
abstract: 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.
authors.affiliation: Department of Cell Biology, Skirball Institute of Biomolecular Medicine, NYU School of Medicine, New York, NY 10016, USA.
authors.forename: Alexandra M
authors.initials: AM
authors.lastname: Pinzaru
authors.affiliation: Department of Chemistry and Biochemistry, University of Colorado, Boulder, CO 80309, USA.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Hom
authors.affiliation: Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: Angela
authors.initials: A
authors.lastname: Beal
authors.affiliation: Department of Cell Biology, Skirball Institute of Biomolecular Medicine, NYU School of Medicine, New York, NY 10016, USA.
authors.forename: Aaron F
authors.initials: AF
authors.lastname: Phillips
authors.affiliation: Department of Biochemistry and Molecular Pharmacology, NYU School of Medicine, New York, NY 10016, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Ni
authors.affiliation: Department of Biochemistry and Molecular Pharmacology, NYU School of Medicine, New York, NY 10016, USA.
authors.forename: Timothy
authors.initials: T
authors.lastname: Cardozo
authors.affiliation: Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: Nidhi
authors.initials: N
authors.lastname: Nair
authors.affiliation: Departments of Dermatology and Biochemistry and Molecular Genetics, Northwestern University, Feinberg School of Medicine, Chicago, IL 60611, USA.
authors.forename: Jaehyuk
authors.initials: J
authors.lastname: Choi
authors.affiliation: Department of Chemistry and Biochemistry, University of Colorado, Boulder, CO 80309, USA.
authors.forename: Deborah S
authors.initials: DS
authors.lastname: Wuttke
authors.affiliation: Department of Cell Biology, Skirball Institute of Biomolecular Medicine, NYU School of Medicine, New York, NY 10016, USA. Electronic address: agnel.sfeir@med.nyu.edu.
authors.forename: Agnel
authors.initials: A
authors.lastname: Sfeir
authors.affiliation: Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA 92037, USA. Electronic address: edenchi@scripps.edu.
authors.forename: Eros Lazzerini
authors.initials: EL
authors.lastname: Denchi
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins / Q000378:metabolism; D063646:Carcinogenesis / Q000378:metabolism* / Q000473:pathology*; D004249:DNA Damage / Q000235:genetics; D004260:DNA Repair / Q000235:genetics; D004261:DNA Replication; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D020022:Genetic Predisposition to Disease; D042822:Genomic Instability; D054503:Lymphoid Progenitor Cells / Q000378:metabolism; D016410:Lymphoma, T-Cell, Cutaneous / Q000235:genetics / Q000276:immunology / Q000473:pathology; D051379:Mice; D050505:Mutant Proteins / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D011485:Protein Binding; D000089804:Shelterin Complex; D013312:Stress, Physiological; D016615:Telomere / Q000378:metabolism*; D034501:Telomere-Binding Proteins; D013950:Thymus Gland / Q000473:pathology; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D050505:Mutant Proteins; C507326:POT1 protein, mouse; D000089804:Shelterin Complex; D034501:Telomere-Binding Proteins; D016159:Tumor Suppressor Protein p53; C576897:Atr protein, mouse; D064007:Ataxia Telangiectasia Mutated Proteins
keywords: ATR; POT1; cutaneous T cell lymphoma; replication stress; telomere; thymic lymphoma