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Cell Rep. 2016 Jun 7;15(10):2170-84. doi: 10.1016/j.celrep.2016.05.008. Epub 2016 May 26.

Telomere Replication Stress Induced by POT1 Inactivation Accelerates Tumorigenesis.

Author information

1
Department of Cell Biology, Skirball Institute of Biomolecular Medicine, NYU School of Medicine, New York, NY 10016, USA.
2
Department of Chemistry and Biochemistry, University of Colorado, Boulder, CO 80309, USA.
3
Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA 92037, USA.
4
Department of Biochemistry and Molecular Pharmacology, NYU School of Medicine, New York, NY 10016, USA.
5
Departments of Dermatology and Biochemistry and Molecular Genetics, Northwestern University, Feinberg School of Medicine, Chicago, IL 60611, USA.
6
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.
7
Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA 92037, USA. Electronic address: edenchi@scripps.edu.

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.

KEYWORDS:

ATR; POT1; cutaneous T cell lymphoma; replication stress; telomere; thymic lymphoma

PMID:
27239034
DOI:
10.1016/j.celrep.2016.05.008
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