title: PML is required for telomere stability in non-neoplastic human cells.
abstract: Telomeres interact with numerous proteins, including components of the shelterin complex, whose alteration, similarly to proliferation-induced telomere shortening, initiates cellular senescence. In tumors, telomere length is maintained by Telomerase activity or by the Alternative Lengthening of Telomeres mechanism, whose hallmark is the telomeric localization of the promyelocytic leukemia (PML) protein. Whether PML contributes to telomeres maintenance in normal cells is unknown. We show that in normal human fibroblasts the PML protein associates with few telomeres, preferentially when they are damaged. Proliferation-induced telomere attrition or their damage due to alteration of the shelterin complex enhances the telomeric localization of PML, which is increased in human T-lymphocytes derived from patients genetically deficient in telomerase. In normal fibroblasts, PML depletion induces telomere damage, nuclear and chromosomal abnormalities, and senescence. Expression of the leukemia protein PML/RARα in hematopoietic progenitors displaces PML from telomeres and induces telomere shortening in the bone marrow of pre-leukemic mice. Our work provides a novel view of the physiologic function of PML, which participates in telomeres surveillance in normal cells. Our data further imply that a diminished PML function may contribute to cell senescence, genomic instability, and tumorigenesis.
authors.affiliation: General Pathology Section, Department of Experimental Medicine, University of Perugia, Perugia, Italy.|Department of Experimental Oncology, European Institute of Oncology, Milan, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Marchesini
authors.affiliation: General Pathology Section, Department of Experimental Medicine, University of Perugia, Perugia, Italy.
authors.forename: R
authors.initials: R
authors.lastname: Matocci
authors.affiliation: General Pathology Section, Department of Experimental Medicine, University of Perugia, Perugia, Italy.|Department of Experimental Oncology, European Institute of Oncology, Milan, Italy.
authors.forename: L
authors.identifier: http://orcid.org/0000-0003-3349-1371
authors.initials: L
authors.lastname: Tasselli
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology, Milan, Italy.
authors.forename: V
authors.initials: V
authors.lastname: Cambiaghi
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology, Milan, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Orleth
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology, Milan, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Furia
authors.affiliation: General Pathology Section, Department of Experimental Medicine, University of Perugia, Perugia, Italy.|Department of Experimental Oncology, European Institute of Oncology, Milan, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Marinelli
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology, Milan, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Lombardi
authors.affiliation: Hematology and Bone Marrow Transplantation Unit, Department of Clinical and Experimental Medicine, University of Parma, Parma, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Sammarelli
authors.affiliation: Hematology and Bone Marrow Transplantation Unit, Department of Clinical and Experimental Medicine, University of Parma, Parma, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Aversa
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology, Milan, Italy.|Department of Biosciences, University of Milan, Milan, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Minucci
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology, Milan, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Faretta
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology, Milan, Italy.|Dipartimento di Medicina, Chirurgia e Odontoiatria, Università degli Studi di Milano, Milan, Italy.
authors.forename: P G
authors.initials: PG
authors.lastname: Pelicci
authors.affiliation: General Pathology Section, Department of Experimental Medicine, University of Perugia, Perugia, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Grignani
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000235:genetics; D002460:Cell Line; D049109:Cell Proliferation / Q000235:genetics; D016922:Cellular Senescence / Q000235:genetics; D042822:Genomic Instability; D006801:Humans; D051379:Mice; D009687:Nuclear Proteins / Q000235:genetics*; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D000071156:Promyelocytic Leukemia Protein; D018168:Receptors, Retinoic Acid / Q000235:genetics*; D000072482:Retinoic Acid Receptor alpha; D013601:T-Lymphocytes / Q000473:pathology; D019098:Telomerase / Q000235:genetics; D016615:Telomere / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics*; D025521:Tumor Suppressor Proteins / Q000235:genetics*
chemical_list: D009687:Nuclear Proteins; D015514:Oncogene Proteins, Fusion; D000071156:Promyelocytic Leukemia Protein; C000607071:RARA protein, human; C000607072:Rara protein, mouse; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C070576:PML protein, human; D019098:Telomerase