AbstractTRF1 and Pin2 play an essential role in telomere homeostasis, by regulating telomere maintenance. They are generated from the same gene, TRF1/Pin2, by alternative splicing but no functional differences between these proteins have been demonstrated. We report here the detection of new alternative transcripts of the TRF1/Pin2 gene in peripheral blood lymphocytes resulting from a 76 nt insertion. Real‐time RT‐PCR showed that these transcripts were also produced in various normal human cells and tissues and in immortalized cell lines, but at levels lower (by a factor of 8–111) than those for the TRF1 and Pin2 transcripts. These new transcripts are predicted to encode polypeptides identical to TRF1/Pin2 at the C‐terminal end but entirely lacking the acid domain and the amino‐terminal part of the homodimerization domain of TRF1/Pin2. These proteins, fused at their N‐terminal ends to enhanced green fluorescent protein (EGFP), were found to be located at telomeres and to induce apoptosis in cell lines with short telomeres, thereby displaying similar activity to TRF1/Pin2. However, these putative proteins lack regions important for interactions with other proteins and for homodimerization. Unlike TRF1/Pin2, they were unable to interact with tankyrase 1, suggesting that these proteins may play a role in telomere homeostasis different from those of TRF1/Pin2. The production of these alternative transcripts was down‐regulated in peripheral blood lymphocytes following PHA‐p activation, suggesting a possible role in resting lymphocytes. © 2004 Wiley‐Liss, Inc.