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TIN2 Protein Dyskeratosis Congenita Missense Mutants Are Defective in Association with Telomerase
- Source :
- Journal of Biological Chemistry. 286:23022-23030
- Publication Year :
- 2011
- Publisher :
- Elsevier BV, 2011.
-
Abstract
- Dyskeratosis congenita (DC) is a progressive and heterogeneous congenital disorder that affects multiple systems and is characterized by bone marrow failure and a triad of abnormal skin pigmentation, nail dystrophy, and oral leukoplakia. One common feature for all DC patients is abnormally short telomeres and defects in telomere biology. Most of the known DC mutations have been found to affect core components of the telomerase holoenzyme. Recently, multiple mutations in the gene encoding the telomeric protein TIN2 have been identified in DC patients with intact telomerase genes, but the molecular mechanisms underlying TIN2 mutation-mediated DC remain unknown. Here, we demonstrate that ectopic expression of TIN2 with DC missense mutations in human cells led to accelerated telomere shortening, similar to the telomere phenotypes found in DC patients. However, this telomere shortening was not accompanied by changes in total telomerase activity, localization of TIN2, or telomere end protection status. Interestingly, we found TIN2 to participate in the TPP1-dependent recruitment of telomerase activity. Furthermore, DC mutations in TIN2 led to its decreased ability to associate with TERC and telomerase activity. Taken together, our data suggest that TIN2 mutations in DC may compromise the telomere recruitment of telomerase, leading to telomere shortening and the associated pathogenesis.
- Subjects :
- Telomere-binding protein
Telomerase
Mutation
Telomere-Binding Proteins
Mutation, Missense
Cell Biology
Telomere
Biology
medicine.disease
medicine.disease_cause
Biochemistry
Molecular biology
Dyskeratosis Congenita
Shelterin Complex
Cell Line
Telomerase RNA component
Cancer research
medicine
Humans
Telomerase reverse transcriptase
Ectopic expression
Molecular Biology
Dyskeratosis congenita
Subjects
Details
- ISSN :
- 00219258
- Volume :
- 286
- Database :
- OpenAIRE
- Journal :
- Journal of Biological Chemistry
- Accession number :
- edsair.doi.dedup.....3b8f419c1d91807715f9c9c33c91d761