Schmutz Isabelle, Mensenkamp Arjen R, Takai Kaori K, Haadsma Maaike, Spruijt Liesbeth, de Voer Richarda M, Choo Seunga Sara, Lorbeer Franziska K, van Grinsven Emma J, Hockemeyer Dirk, Jongmans Marjolijn Cj, de Lange Titia
Laboratory for Cell Biology and Genetics, Rockefeller University, New York, United States.
Department of Human Genetics, Radboud University Medical Center, Nijmegen, Netherlands.
Elife. 2020 Dec 1;9:e61235. doi: 10.7554/eLife.61235.
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 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 resulted in excessive telomere elongation in clonal lines, indicating that is haploinsufficient for telomere length control. In contrast, telomere protection and genome stability were maintained in all heterozygous clones. The data establish that the truncations predispose to a tumor syndrome. We conclude that acts as a haploinsufficient tumor suppressor that limits telomere length to ensure a timely Hayflick limit.
端粒缩短是一种推测的肿瘤抑制途径，在肿瘤发生过程中施加增殖屏障（海弗利克极限）。该模型预测，过长的体细胞端粒易患癌症。在此，我们描述了具有两个独特突变的癌症易感家族，这些突变截断了TIN2，TIN2是一种控制端粒长度的端粒保护蛋白亚基。患者淋巴细胞端粒异常长。我们发现截断的TIN2蛋白不能定位于端粒，这表明这些突变产生了功能丧失等位基因。突变的杂合敲入或一个拷贝的缺失导致克隆系中端粒过度延长，表明TIN2在端粒长度控制方面单倍剂量不足。相反，所有杂合克隆中的端粒保护和基因组稳定性均得以维持。这些数据证实，TIN2截断易患肿瘤综合征。我们得出结论，TIN2作为一种单倍剂量不足的肿瘤抑制因子，限制端粒长度以确保及时达到海弗利克极限。
