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Telomerase activation plays a critical role in tumorigenesis.The expression of the human telomerase reverse transcriptase catalytic subunit (hTERT) is well-correlated with telomerase enzymatic activity.To test the expression of hTERT mRNA in the early stages of lung cancer development, we used in situ hybridization to analyze hTERT expression in bronchial biopsies from smokers.Unexpectedly, not only did an antisense hTERT probe consistently show a positive signal in the tissues tested but a sense hTERT probe did as well.This observation led us to investigate whether an antisense hTERT RNA transcript was present in the tissues tested.Here, we provide several lines of evidence supporting the existence of such a transcript and the first identification of a cis antisense transcript transcribed from the opposite strand ofintron 3 of the hTERT gene.We also demonstrate that this antisense transcript of hTERT (TERT-AS) encodes a protein whose expression appears to be inversely correlated with the expression of hTERT in both cell lines and primary cancer tissues, including in cell lines which utilize the alternative telomere-lengthening mechanism (ALT).Furthermore, silencing of TERT-AS led to an elevation in the expression of the hTERT transcript as well as its protein.The increase in TERT protein was associated with an increase in telomerase activity.Conversely, overexpression of TERT-AS resulted in a decrease in the expression of both the hTERT transcript and protein, leading to a decline in telomerase activity and the appearance of the ALT phenotype.These findings suggest that hTERT expression may be under the control of a natural antisense transcript that also appears to play a role in the emergence of the ALT phenotype.