TINF2 is a haploinsufficient tumor suppressor that limits telomere length.

Autor:	Schmutz I; Laboratory for Cell Biology and Genetics, Rockefeller University, New York, United States., Mensenkamp AR; Department of Human Genetics, Radboud University Medical Center, Nijmegen, Netherlands., Takai KK; Laboratory for Cell Biology and Genetics, Rockefeller University, New York, United States., Haadsma M; Department of Human Genetics, Radboud University Medical Center, Nijmegen, Netherlands., Spruijt L; Department of Human Genetics, Radboud University Medical Center, Nijmegen, Netherlands., de Voer RM; Department of Human Genetics, Radboud University Medical Center, Nijmegen, Netherlands., Choo SS; Department of Molecular and Cellular Biology, University of California, Berkeley, Berkeley, United States., Lorbeer FK; Department of Molecular and Cellular Biology, University of California, Berkeley, Berkeley, United States., van Grinsven EJ; Department of Molecular and Cellular Biology, University of California, Berkeley, Berkeley, United States., Hockemeyer D; Department of Molecular and Cellular Biology, University of California, Berkeley, Berkeley, United States.; Chan Zuckerberg Biohub, San Francisco, United States., Jongmans MC; Department of Human Genetics, Radboud University Medical Center, Nijmegen, Netherlands., de Lange T; Laboratory for Cell Biology and Genetics, Rockefeller University, New York, United States.
Jazyk:	angličtina
Zdroj:	ELife [Elife] 2020 Dec 01; Vol. 9. Date of Electronic Publication: 2020 Dec 01.
DOI:	10.7554/eLife.61235
Abstrakt:	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. Competing Interests: IS, AM, KT, MH, LS, Rd, SC, FL, Ev, DH, MJ No competing interests declared, Td Member of the SAB of Calico Life Sciences LLC (© 2020, Schmutz et al.)
Databáze:	MEDLINE
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