TINF2 is a haploinsufficient tumor suppressor that limits telomere length.
TINF2 is a haploinsufficient tumor suppressor that limits telomere length.
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DOI：
10.7554/elife.61235
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发表时间：
2020-12-01
期刊：
影响因子：
7.7
通讯作者：
de Lange T
中科院分区：
文献类型：
--
作者：
Schmutz I;Mensenkamp AR;Takai KK;Haadsma M;Spruijt L;de Voer RM;Choo SS;Lorbeer FK;van Grinsven EJ;Hockemeyer D;Jongmans MC;de Lange T
端粒缩短是一种假定的肿瘤抑制途径，在肿瘤发生期间施加增殖屏障（Hayflick限制）。该模型预测，过长的体细胞端粒易患癌症。在这里，我们描述了具有两个独特的TINF2突变的癌症易感家族，TIN2是一种控制端粒长度的庇护素亚基。患者淋巴细胞端粒异常长。我们发现截短的TIN 2蛋白不定位于端粒，这表明突变产生了功能丧失的等位基因。杂合敲入突变或删除一个拷贝的TINF2导致克隆系中的过度端粒延长，表明TINF2对于端粒长度控制是单倍不足的。相反，端粒保护和基因组稳定性保持在所有杂合克隆。数据证实，TINF2截短易患肿瘤综合征。我们的结论是，TINF2作为一个单倍不足的肿瘤抑制，限制端粒长度，以确保及时海弗利克限制。
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.