A POT1 mutation implicates defective telomere end fill-in and telomere truncations in Coats plus

Hiroyuki Takai; Emma Jenkinson; Shaheen Kabir; Riyana Babul-Hirji; Nasrin Najm-Tehrani; David A. Chitayat; Yanick J. Crow; Titia de Lange

doi:10.1101/gad.276873.115

A POT1 mutation implicates defective telomere end fill-in and telomere truncations in Coats plus

¹The Rockefeller University, New York, New York 10065, USA;
²Manchester Centre for Genomic Medicine, Institute of Human Development, Faculty of Medical and Human Sciences, Manchester Academic Health Sciences Centre, University of Manchester, Manchester M13 9PT, United Kingdom;
³Department of Pediatrics, Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, University of Toronto, Toronto, Ontario M5G 1Z5, Canada;
⁴Department of Pediatrics, Division of Opthalmology and Visions Sciences, The Hospital for Sick Children, University of Toronto, Toronto, Ontario M5G 1Z5, Canada;
⁵The Prenatal Diagnosis and Medical Genetics Program, Department of Obstetrics and Gynecology, Mount Sinai Hospital, University of Toronto, Toronto, Ontario M5G 1X5, Canada;
⁶Department of Paediatrics, Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, University of Toronto, Toronto, Ontario M5G 1Z5, Canada;
⁷UMR 1163, Institut National de la Santé et de la Recherche Médicale, Laboratory of Neurogenetics and Neuroinflammation, Paris Descartes-Sorbonne Paris Cité University, Institut Imagine, Hôpital Necker, Paris 75015, France

Corresponding authors: delange{at}rockefeller.edu, yanickcrow{at}mac.com

↵8 These authors contributed equally to this work.
↵9 These authors contributed equally to this work.

Abstract

Coats plus (CP) can be caused by mutations in the CTC1 component of CST, which promotes polymerase α (polα)/primase-dependent fill-in throughout the genome and at telomeres. The cellular pathology relating to CP has not been established. We identified a homozygous POT1 S322L substitution (POT1^CP) in two siblings with CP. POT1^CP induced a proliferative arrest that could be bypassed by telomerase. POT1^CP was expressed at normal levels, bound TPP1 and telomeres, and blocked ATR signaling. POT1^CP was defective in regulating telomerase, leading to telomere elongation rather than the telomere shortening observed in other telomeropathies. POT1^CP was also defective in the maintenance of the telomeric C strand, causing extended 3′ overhangs and stochastic telomere truncations that could be healed by telomerase. Consistent with shortening of the telomeric C strand, metaphase chromosomes showed loss of telomeres synthesized by leading strand DNA synthesis. We propose that CP is caused by a defect in POT1/CST-dependent telomere fill-in. We further propose that deficiency in the fill-in step generates truncated telomeres that halt proliferation in cells lacking telomerase, whereas, in tissues expressing telomerase (e.g., bone marrow), the truncations are healed. The proposed etiology can explain why CP presents with features distinct from those associated with telomerase defects (e.g., dyskeratosis congenita).

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Footnotes

Supplemental material is available for this article.
Article published online ahead of print. Article and publication date are online at http://www.genesdev.org/cgi/doi/10.1101/gad.276873.115.

Received December 21, 2015.
Accepted March 2, 2016.

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