Kathleen Collins

Walter and Ruth Schubert Family Chair
Professor of Biochemistry, Biophysics and Structural Biology
Department of Molecular and Cell Biology
University of California, Berkeley

 

Human telomerase RNA (hTER) contains an H/ACA domain crucial for TER processing and biological stability. Patients with the bone marrow failure syndrome dyskeratosis congenita (DC) suffer a progressive loss of hematopoietic renewal. The predominant X-linked form of DC is caused by mutations in dyskerin, a protein that binds to the H/ACA motif. We found that disease-linked isoforms of dyskerin specifically compromise telomerase RNP biogenesis, and that DC patient cells have critically short telomeres. Telomerase activation in DC patient cells failed to elongate telomeres, in contrast to family-matched control cells. We showed that this defect could be rescued by supplemental expression of hTER.. Our findings reveal that telomere maintenance in primary human somatic cells becomes limited by a few-fold decrease in hTER level, and support to the idea of telomerase activation as a clinically useful therapeutic. We are currently studying the impact of mutations in hTER itself, which have been more recently discovered in other disease states characterized by hematopoietic failure.