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My research is directed to understanding the roles of ribosome biogenesis and telomere maintenance in human disease. We are particularly interested in the genetics and pathogenesis of two inherited bone marrow failure syndromes, namely dyskeratosis congenita and Diamond Blackfan Anemia.

Dyskeratosis congenita has X-linked, autosomal dominant and recessive forms. We have identified a gene DKC1, which encodes a protein called dyskerin, that is responsible for the X-linked form of the disease. Dyskerin is a nucleolar protein that is part of snoRNAs that are important in ribosomal RNA processing. Dyskerin is also part of the telomerase complex that maintains the integrity of the telomeres that cap the chomosome ends. We use cell and molecular biological approaches to study the mechanisms by which dyskerin modifies newly synthesized ribosomal RNA and stabilizes the telomerase complex. By studying the consequences of dyskerin mutations in cell and animal models we hope to understand the pathogenesis of DC and the roles of ribosome biogenesis and telomere maintenance in normal physiology. We have recently found that a dyskerin mutation that causes DC in humans causes a growth defect in mice which is telomerase dependent but independent of telomere length. The mutation also leads to an increase in the number of DNA damage foci at telomeres. This suggests a novel role for dyskerin in telomere maintenance.

Diamond Blackfan Anemia is a pure red cell aplasia which presents usually in childhood, sometimes with a variety of associated developmental abnormalities. Recently mutations in several ribosomal proteins from either subunit have been found to cause DBA. We wish to understand how mutations in ribosomal proteins give rise to failure of erythropoiesis. We use cell and animal models to study the role of ribosomal proteins in ribosome biogenesis and function. We have recently studied the effect of depleting cells of specific ribosomal proteins. We find that in all cases production of the ribosome subunit where the protein resides is inhibited with the degradation of other proteins from the same subunit. We conclude DBA, in which individual ribosomal proteins are haploinsufficient, results from a failure of ribosome biogenesis. We are now using erythroid cell lines to study why inefficient ribosome biogenesis should specifically effect red cell development.

The relationship between H/ACA snoRNPs and telomerase RNPs Telomerase RNA has a H/ACA box sequence at its 3' end and is associated with the same 4 proteins that are present in the snoRNP. Other proteins are present in the telomerase complex including the telomerase reverse transcriptase TERT. From: Mason PJ, Wilson DB, Bessler M Dyskeratosis congenita -- a disease of dysfunctional telomere maintenance. Curr Mol Med 2005 Mar;5(2):159-70

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• Updated: June 19, 2009
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