is a Haploinsufficient Tumor Suppressor That Limits Telomere Length

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.