Tinf2 is a haploinsufficient tumor suppressor that limits telomere length

Isabelle Schmutz, Arjen R. Mensenkamp, Kaori K. Takai, Maaike Haadsma, Liesbeth Spruijt, Richarda M. De Voer, Seunga Sara Choo, Franziska K. Lorbeer, Emma J. Van Grinsven, Dirk Hockemeyer, Marjolijn Cj Jongmans, Titia De Lange

Onderzoeksoutput: Bijdrage aan tijdschriftArtikelpeer review

27 Citaten (Scopus)

Samenvatting

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 ength. 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.

Originele taal-2Engels
Artikelnummere61235
Pagina's (van-tot)1-20
Aantal pagina's20
TijdschrifteLife
Volume9
DOI's
StatusGepubliceerd - dec. 2020
Extern gepubliceerdJa

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