1. Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA

Correspondence to: Zhou Songyang¹ Correspondence and requests for materials should be addressed to Z.S. (Email: songyang@bcm.tmc.edu).

Telomere dysfunction may result in chromosomal abnormalities, DNA damage responses, and even cancer¹. Early studies in lower organisms have helped to establish the crucial role of telomerase and telomeric proteins in maintaining telomere length and protecting telomere ends^{2, 3, 4, 5, 6, 7}. In Oxytricha nova, telomere G-overhangs are protected by the TEBP-/ heterodimer^{3, 4}. Human telomeres contain duplex telomeric repeats with 3' single-stranded G-overhangs, and may fold into a t-loop structure that helps to shield them from being recognized as DNA breaks^{8, 9}. Additionally, the TEBP- homologue, POT1, which binds telomeric single-stranded DNA (ssDNA)¹⁰, associates with multiple telomeric proteins (for example, TPP1, TIN2, TRF1, TRF2 and RAP1) to form the six-protein telosome/shelterin^{11, 12} and other subcomplexes. These telomeric protein complexes in turn interact with diverse pathways to form the telomere interactome¹³ for telomere maintenance. However, the mechanisms by which the POT1-containing telosome communicates with telomerase to regulate telomeres remain to be elucidated. Here we demonstrate that TPP1 is a putative mammalian homologue of TEBP- and contains a predicted amino-terminal oligonucleotide/oligosaccharide binding (OB) fold. TPP1–POT1 association enhanced POT1 affinity for telomeric ssDNA. In addition, the TPP1 OB fold, as well as POT1–TPP1 binding, seemed critical for POT1-mediated telomere-length control and telomere-end protection in human cells. Disruption of POT1–TPP1 interaction by dominant negative TPP1 expression or RNA interference (RNAi) resulted in telomere-length alteration and DNA damage responses. Furthermore, we offer evidence that TPP1 associates with the telomerase in a TPP1-OB-fold-dependent manner, providing a physical link between telomerase and the telosome/shelterin complex. Our findings highlight the critical role of TPP1 in telomere maintenance, and support a yin–yang model in which TPP1 and POT1 function as a unit to protect human telomeres, by both positively and negatively regulating telomerase access to telomere DNA.

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