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

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

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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.Oncogene advance online publication, 29 June 2015; doi:10.1038/onc.2015.246.

Original languageEnglish
Publication statusAccepted/In press - Jun 29 2015

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

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    Marchesini, M., Matocci, R., Tasselli, L., Cambiaghi, V., OrlethOrleth, A., Furia, L., Marinelli, C., Lombardi, S., Sammarelli, G., Aversa, F., Minucci, S., Faretta, M., Pelicci, P. G., & Grignani, F. (Accepted/In press). PML is required for telomere stability in non-neoplastic human cells. Oncogene.