TPP1 is a homologue of ciliate TEBP-β and interacts with POT1 to recruit telomerase

Abstract

Telomere dysfunction may result in chromosomal abnormalities, DNA damage responses, and even cancer. 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. In Oxytricha nova, telomere G-overhangs are protected by the TEBP-alpha/beta heterodimer. 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. Additionally, the TEBP-alpha homologue, POT1, which binds telomeric single-stranded DNA (ssDNA), associates with multiple telomeric proteins (for example, TPP1, TIN2, TRF1, TRF2 and RAP1) to form the six-protein telosome/shelterin and other subcomplexes. These telomeric protein complexes in turn interact with diverse pathways to form the telomere interactome 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-beta 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.

Telomerase stimulates ribosomal DNA transcription under hyperproliferative conditions

“…2b). Note that telomerase is recruited to telomere ends during the S-phase to function in telomere elongation 7,13,14 . Thus, telomere binding of telomerase can only be detected in liver ChIP/Re-ChIP assay tumours containing highly proliferative cells and not in normal livers containing resting cells, despite comparable levels of telomerase in both mouse samples (see Fig.…”

Dyskerin Is a Component of the Arabidopsis Telomerase RNP Required for Telomere Maintenance

“…AtPOT1a is an OB-fold-bearing protein that physically interacts with catalytically active telomerase in Arabidopsis and promotes enzyme function in vitro and in vivo (43). Recent studies indicate that human telomerase associates with TPP1, an hPOT1 binding partner that also harbors an OB-fold motif (48,50). Whether the human dyskerin contacts TPP1 is unknown.…”

Anthracyclines disrupt telomere maintenance by telomerase through inducing PinX1 ubiquitination and degradation

“…Therefore, communication with the shelterin complex is an essential step for the telomerase to carry out its telomere maintenance action. Recent studies have revealed that in addition to participating in the shelterin formation, the Pot1-TPP1 heterodimers have crucial roles in recruiting telomerase function on telomeres (Xin et al, 2007). The studies suggest that the Pot1-TPP1 dimer may function as the telomerase receptor at telomeres for guiding this enzyme's access to its functional default substrates.…”