Telomere Replication Stress Induced by POT1 Inactivation Accelerates Tumorigenesis

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

*Corresponding author for this work

Research output: Contribution to journalArticle

39 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)2170-2184
Number of pages15
JournalCell reports
Volume15
Issue number10
DOIs
StatePublished - Jun 7 2016

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Keywords

  • ATR
  • Cutaneous T cell lymphoma
  • POT1
  • Replication stress
  • Telomere
  • Thymic lymphoma

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Pinzaru, A. M., Hom, R. A., Beal, A., Phillips, A. F., Ni, E., Cardozo, T., Nair, N., Choi, J., Wuttke, D. S., Sfeir, A., & Denchi, E. L. (2016). Telomere Replication Stress Induced by POT1 Inactivation Accelerates Tumorigenesis. Cell reports, 15(10), 2170-2184. https://doi.org/10.1016/j.celrep.2016.05.008