@article{bbc2b97f52374b9890f15ce183fe0c22,
title = "Telomere Replication Stress Induced by POT1 Inactivation Accelerates Tumorigenesis",
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, Cutaneous T cell lymphoma, POT1, Replication stress, Telomere, Thymic lymphoma",
author = "Pinzaru, {Alexandra M.} and Hom, {Robert A.} and Angela Beal and Phillips, {Aaron F.} and Eric Ni and Timothy Cardozo and Nidhi Nair and Jaehyuk Choi and Wuttke, {Deborah S.} and Agnel Sfeir and Denchi, {Eros Lazzerini}",
note = "Funding Information: We thank Titia de Lange, Joachim Lingner, Changchung Xiao, and Jerold Chun for providing critical reagents for this study. We thank Lauren Pitt, Markos Al-Far, and Angela Hin for technical assistance. We are grateful to Elena Federzoni and Bruce Torbett for support with the characterization of thymic lymphomas and Jonathan Hart and Andrew Routh for help in analyzing the RNA-seq data. We thank Susan Schwab, Shaheen Kabir, and members of the E.L-D. and A.S. labs for commenting on the manuscript. This work was supported by grants from the NIH for E.L.-D. (AG038677), A.S. (CA195767), and D.S.W. (GM059414). A.M.P. was supported by a NYSTEM institutional training grant (C026880). A.B. was supported by a CIRM scholarship, and R.A.H. was supported by the Ruth L. Kirschstein National Research Service Award (GM100532). Additional support was provided by the V-Foundation to A.S., by a Pew-Stewart Scholars Award to A.S., by a Pew Scholars Award to E.L.-D., and by the Novartis Advanced Discovery Institute to E.L.-D. ",
year = "2016",
month = jun,
day = "7",
doi = "10.1016/j.celrep.2016.05.008",
language = "English (US)",
volume = "15",
pages = "2170--2184",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "10",
}