@article{c047d0aea95f450fae715899f96f6b40,
title = "TINF2 is a haploinsufficient tumor suppressor that limits telomere length",
abstract = "Telomere shortening is a presumed tumor suppressor pathway that imposes a proliferative barrier (the Hayflick limit) during tumorigenesis. This model predicts that excessively long somatic telomeres predispose to cancer. Here, we describe cancer-prone families with two unique TINF2 mutations that truncate TIN2, a shelterin subunit that controls telomere length. Patient lymphocyte telomeres were unusually long. We show that the truncated TIN2 proteins do not localize to telomeres, suggesting that the mutations create loss-of-function alleles. Heterozygous knock-in of the mutations or deletion of one copy of TINF2 resulted in excessive telomere elongation in clonal lines, indicating that TINF2 is haploinsufficient for telomere length control. In contrast, telomere protection and genome stability were maintained in all heterozygous clones. The data establish that the TINF2 truncations predispose to a tumor syndrome. We conclude that TINF2 acts as a haploinsufficient tumor suppressor that limits telomere length to ensure a timely Hayflick limit.",
keywords = "TIN2, cancer biology, cancer predisposition, human, telomere length",
author = "Isabelle Schmutz and Mensenkamp, {Arjen R} and Takai, {Kaori K} and Maaike Haadsma and Liesbeth Spruijt and {de Voer}, {Richarda M} and Choo, {Seunga Sara} and Lorbeer, {Franziska K} and {van Grinsven}, {Emma J} and Dirk Hockemeyer and Jongmans, {Marjolijn Cj} and {de Lange}, Titia",
note = "Funding Information: We thank the members of the de Lange lab for helpful discussion. John Zinder is thanked for generating the structural representation of the TIN2 truncations. Research reported in this publication was supported by grants from the NCI (R35CA210036), the Breast Cancer Research Foundation, and the Melanoma Research Alliance (MRA 577521) to T.d.L. T.d.L. is an American Cancer Society Rose Zar-ucki Trust Research Professor. D.H. is a Chan Zuckerburg Biohub Investigator, a Pew-Stewart Scholar for Cancer Research supported by the Pew Charitable Trusts and the Alexander and Margaret Stewart Trust. This research is supported by grants to D.H. from the Siebel Stem Cell Institute, the NIH (R01-CA196884), the D.O.D. (W81XWH-19-1-0586), and a Research Scholar Grants from the American Cancer Society (133396-RSG-19-029-01-DMC). Funding Information: NIHR01-CA196884, U.S. Department of DefenseW81XWH-19-1-0586, American Cancer Society133396-RSG-19-029-01-DMC, National Cancer InstituteR35CA210036 Publisher Copyright: {\textcopyright} Schmutz et al.",
year = "2020",
month = dec,
day = "1",
doi = "10.7554/eLife.61235",
language = "English",
volume = "9",
pages = "1--20",
journal = "eLife",
issn = "2050-084X",
publisher = "eLife Sciences Publications",
}