RNA level limits telomere maintenance in X-linked dyskeratosis congenita.
Judy M.Y. Wong and Kathleen Collins (UC Berkeley)
Genes and Development 20:2848-2858, 2006. (Published online Oct 2, 2006)
The inherited syndrome dyskeratosis congenita (DC) is characterized by bone marrow failure and skin findings such as rash, and nail and pigmentation abnormalities. Dyskerin is the gene responsible for the X-linked form of DC. Dyskerin is a presumed pseudouridine synthase enzyme that modifies rRNAs and also is associated with the telomerase complex.
The culprit behind the collapse of bone marrow cell production has been the subject of debate- is it defective ribosome generation or decreased telomerase activity that is responsible? In a step towards settling this issue, Wong and Collins now show that DC patient cells have considerably shortened life spans in culture but normal ribosome formation. Introduction of the telomerase RNA component (TER), along with the catalytic reverse transcriptase protein (TERT), dramatically rescues their proliferative competence and telomere shortening.
Primary fibroblasts cultured from DC patients undergo senescence more rapidly than control cells. The catalytic component of telomerase, TERT, can extend the lifespan of these cells in culture. However, TERT alone does not maintain or lengthen the cells' shortened telomeres. Expressing TER in addition to TERT rescues telomere shortening in DC cells.
The critical tool for this study was generation of DC cells with restored proliferative capacity. The authors were now able to look for alterations in ribosome biogenesis in comparison to control cells with matching proliferative potential. This avoided confounding ribosome changes due to the decreased proliferative potential of (native) DC cells. Interestingly, X-linked DC patient cells did not show defects in ribosome formation, suggesting that diminished telomerase activity is a major contributor to the disease.
These studies indicate that supplementing telomerase activity in X-linked DC patients may be a potential therapeutic option for this fatal disease.
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