Telomere, the end of linear chromosome, is protected by DNA-protein complexes. These complexes cap the linear chromosome and play an important role in the maintenance of genomic stability. TRF1/PIN2, a double-stranded DNA-binding protein is known to regulate telomere length by not only protecting telomere but also blocking the access of telomerase to telomere in cis. To better understand the mechanism through which TRF1/PIN2 regulates telomere length, we performed the yeast two-hybrid screening and identified the transcriptional activator c-Myc as a TRF1/PIN2-binding protein. The c-Myc-TRF1/PIN2 interaction was observed both in vitro and in vivo. This interaction is mediated by the basic helix-loop-helix (bHLH) domain of c-Myc. Importantly, overexpression of this TRF1/PIN2-interacting domain of c-Myc leads to telomere elongation in vivo. Together, these results suggest that c-Mye may be involved in the regulation of telomere length through its direct binding with TRF1/PIN2. (c) 2007 Elsevier Inc. All rights reserved.