Document Detail

TIN2 protein dyskeratosis congenita missense mutants are defective in association with telomerase.
MedLine Citation:
PMID:  21536674     Owner:  NLM     Status:  MEDLINE    
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.
Dong Yang; Quanyuan He; Hyeung Kim; Wenbin Ma; Zhou Songyang
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2011-05-02
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  286     ISSN:  1083-351X     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2011 Jul 
Date Detail:
Created Date:  2011-06-27     Completed Date:  2011-09-09     Revised Date:  2013-06-30    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  23022-30     Citation Subset:  IM    
Verna and Mars McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, Texas 77030, USA.
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MeSH Terms
Aminopeptidases / genetics,  metabolism
Cell Line
Dipeptidyl-Peptidases and Tripeptidyl-Peptidases / genetics,  metabolism
Dyskeratosis Congenita / genetics,  metabolism*
Mutation, Missense*
Serine Proteases / genetics,  metabolism
Telomerase / genetics,  metabolism
Telomere / genetics,  metabolism*
Telomere-Binding Proteins / genetics,  metabolism*
Grant Support
Reg. No./Substance:
0/TINF2 protein, human; 0/Telomere-Binding Proteins; EC; EC 3.4.-/Serine Proteases; EC 3.4.11.-/Aminopeptidases; EC 3.4.14.-/Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; EC 1

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