Dyskeratosis congenita (DC) is a severe, inherited, bone marrow failure syndrome, with associated cutaneous and noncutaneous abnormalities. DC patients also show signs of premature aging and have an increased occurrence of cancer. Accelerated telomeric erosion is a molecular hallmark of DC (Mitchell et al., 1999; Ruggero et al.,
2003). DC can originate through (i) mutations in DKC1, which result in X-linked recessive DC; (ii) mutations in the RNA component of telomerase (TERC), which result in autosomal dominant DC; and (iii) mutations in other, currently uncharacterized, genes, which result in autosomal recessive DC. As DKC1 encodes dyskerin, a protein component of small nucleolar ribonucleoprotein (snoRNP) particles, which are important in ribosomal RNA processing, DC was initially described as a disorder of defective ribosomal biogenesis. Subsequently, dyskerin and TERC were shown to closely associate with each other in the telomerase complex, and DC has since come to be regarded as a telomerase deficiency disorder characterized by shorter telomeres. These findings demonstrate the importance of telomerase in humans and highlight how its deficiency (through DKC1 and TERC mutations) results in multiple abnormalities including premature aging, bone marrow failure and cancer. Identification of the gene(s) involved in autosomal recessive DC will help to define the pathophysiology of DC further, as well as expand our insights into telomere function, aging and cancer. Through the challenge with targeted knockdown of zebrafish telomerase, it is likely that a novel vertebrate model system can be developed for studies of DC. In this respect, studies of evolutionary and comparative biology in telomerase and telomere metabolism are important because zebrafish have a constitutive telomerase activity that is apparently different from the human telomerase regulation. There is first and foremost a need to compare the importance of telomerase in zebrafish and in humans, by trying to recapitulate DC phenotypes in a zebrafish model.
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