<i>TINF2</i> 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 <i>TINF2</i> 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 <i>TINF2</i> resulted in excessive telomere elongation in clonal lines, indicating that <i>TINF2</i> is haploinsufficient for telomere length control. In contrast, telomere protection and genome stability were maintained in all heterozygous clones. The data establish that the <i>TINF2</i> truncations predispose to a tumor syndrome. We conclude that <i>TINF2</i> acts as a haploinsufficient tumor suppressor that limits telomere length to ensure a timely Hayflick limit.