TINF2 is a haploinsufficient tumor suppressor that limits telomere length
| Autor: | Maaike Haadsma, Franziska K. Lorbeer, Marjolijn C.J. Jongmans, Seung-A Sara Choo, Richarda M. de Voer, Titia de Lange, Emma J van Grinsven, Dirk Hockemeyer, Kaori K. Takai, Isabelle Schmutz, Arjen R. Mensenkamp, Liesbeth Spruijt |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
QH301-705.5 Somatic cell Science cancer predisposition TINF2 Biology medicine.disease_cause General Biochemistry Genetics and Molecular Biology law.invention 03 medical and health sciences All institutes and research themes of the Radboud University Medical Center 0302 clinical medicine law Tumours of the digestive tract Radboud Institute for Molecular Life Sciences [Radboudumc 14] telomere length medicine TIN2 Biology (General) Cancer Biology Women's cancers Radboud Institute for Molecular Life Sciences [Radboudumc 17] General Immunology and Microbiology General Neuroscience General Medicine Hayflick limit Shelterin Telomere Cell biology 030104 developmental biology Medicine Suppressor Haploinsufficiency Carcinogenesis 030217 neurology & neurosurgery Research Article Human Rare cancers Radboud Institute for Health Sciences [Radboudumc 9] |
| Zdroj: | Elife, 9 eLife, Vol 9 (2020) eLife |
| ISSN: | 2050-084X |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|