PML is required for telomere stability in non-neoplastic human cells

M. Marchesini, R. Matocci, L. Tasselli, V Cambiaghi, Annette Orleth, L Furia, C Marinelli, S. Lombardi, Gabriella Sammarelli, F. Aversa, S Minucci, M Faretta, P G Pelicci, F. Grignani

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)1811-21
Number of pages11
JournalOncogene
Volume35
Issue number14
DOIs
Publication statusPublished - Apr 7 2016

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Telomere
Leukemia
Telomere Shortening
Cell Aging
Telomerase
Fibroblasts
Telomere Homeostasis
Genomic Instability
Chromosome Aberrations
Carcinogenesis
Bone Marrow
Maintenance
T-Lymphocytes

Keywords

  • Animals
  • Carcinogenesis
  • Cell Aging
  • Cell Line
  • Cell Proliferation
  • Genomic Instability
  • Humans
  • Mice
  • Nuclear Proteins
  • Oncogene Proteins, Fusion
  • Promyelocytic Leukemia Protein
  • Receptors, Retinoic Acid
  • Retinoic Acid Receptor alpha
  • T-Lymphocytes
  • Telomerase
  • Telomere
  • Transcription Factors
  • Tumor Suppressor Proteins
  • Journal Article
  • Research Support, Non-U.S. Gov't

Cite this

Marchesini, M., Matocci, R., Tasselli, L., Cambiaghi, V., Orleth, A., Furia, L., ... Grignani, F. (2016). PML is required for telomere stability in non-neoplastic human cells. Oncogene, 35(14), 1811-21. https://doi.org/10.1038/onc.2015.246

PML is required for telomere stability in non-neoplastic human cells. / Marchesini, M.; Matocci, R.; Tasselli, L.; Cambiaghi, V; Orleth, Annette; Furia, L; Marinelli, C; Lombardi, S.; Sammarelli, Gabriella; Aversa, F.; Minucci, S; Faretta, M; Pelicci, P G; Grignani, F.

In: Oncogene, Vol. 35, No. 14, 07.04.2016, p. 1811-21.

Research output: Contribution to journalArticle

Marchesini, M, Matocci, R, Tasselli, L, Cambiaghi, V, Orleth, A, Furia, L, Marinelli, C, Lombardi, S, Sammarelli, G, Aversa, F, Minucci, S, Faretta, M, Pelicci, PG & Grignani, F 2016, 'PML is required for telomere stability in non-neoplastic human cells', Oncogene, vol. 35, no. 14, pp. 1811-21. https://doi.org/10.1038/onc.2015.246
Marchesini M, Matocci R, Tasselli L, Cambiaghi V, Orleth A, Furia L et al. PML is required for telomere stability in non-neoplastic human cells. Oncogene. 2016 Apr 7;35(14):1811-21. https://doi.org/10.1038/onc.2015.246
Marchesini, M. ; Matocci, R. ; Tasselli, L. ; Cambiaghi, V ; Orleth, Annette ; Furia, L ; Marinelli, C ; Lombardi, S. ; Sammarelli, Gabriella ; Aversa, F. ; Minucci, S ; Faretta, M ; Pelicci, P G ; Grignani, F. / PML is required for telomere stability in non-neoplastic human cells. In: Oncogene. 2016 ; Vol. 35, No. 14. pp. 1811-21.
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AU - Tasselli, L.

AU - Cambiaghi, V

AU - Orleth, Annette

AU - Furia, L

AU - Marinelli, C

AU - Lombardi, S.

AU - Sammarelli, Gabriella

AU - Aversa, F.

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AU - Faretta, M

AU - Pelicci, P G

AU - Grignani, F.

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