Dyskeratosis congenita (DC) is characterized by the triad of reticulate skin 
pigmentation, nail dystrophy and leukoplakia. Epidermal atrophy, hair growth 
defects, bone marrow failure and increased risk of cancer are also common in DC 
patients. DC is caused by mutations in genes encoding for telomerase complex 
factors. Although there is an association of epidermal abnormalities with DC, 
epidermal cells from DC donors have not been previously characterized. We have 
isolated skin keratinocytes from affected members of a family with an autosomal 
dominant form of DC that is caused by a mutation in the RNA component of 
telomerase, TERC. Here, we demonstrate that, similar to DC fibroblasts from 
these donors, DC keratinocytes have short telomeres and a short lifespan. DC 
keratinocytes also exhibited impaired colony forming efficiency (CFE) and 
migration capacity. Exogenous expression of the reverse transcriptase (RT) 
component of telomerase, TERT, activated telomerase levels to half that of TERT 
expressing normal cells and maintained telomeres at a short length with 
concomitant extension of lifespan. Unlike fibroblasts, transduction of human 
papillomavirus type 16 E6/E7 genes into DC keratinocytes activated telomerase to 
half that of E6/E7 expressing normal cells, and robust proliferation was 
observed. While expression of TERC has no measurable effect on telomerase in 
fibroblasts, expression of TERC in keratinocytes upregulated telomerase activity 
and, rarely, allowed rescue of proliferative defects. Our results point to 
important differences between DC fibroblasts and keratinocytes and show, for the 
first time, that expression of TERC can increase the lifespan of primary human 
epithelial cells.