The POT1–TPP1 telomere complex is a telomerase processivity factor

Abstract

Telomeres were originally defined as chromosome caps that prevent the natural ends of linear chromosomes from undergoing deleterious degradation and fusion events. POT1 (protection of telomeres) protein binds the single-stranded G-rich DNA overhangs at human chromosome ends and suppresses unwanted DNA repair activities. TPP1 is a previously identified binding partner of POT1 that has been proposed to form part of a six-protein shelterin complex at telomeres. Here, the crystal structure of a domain of human TPP1 reveals an oligonucleotide/oligosaccharide-binding fold that is structurally similar to the beta-subunit of the telomere end-binding protein of a ciliated protozoan, suggesting that TPP1 is the missing beta-subunit of human POT1 protein. Telomeric DNA end-binding proteins have generally been found to inhibit rather than stimulate the action of the chromosome end-replicating enzyme, telomerase. In contrast, we find that TPP1 and POT1 form a complex with telomeric DNA that increases the activity and processivity of the human telomerase core enzyme. We propose that POT1-TPP1 switches from inhibiting telomerase access to the telomere, as a component of shelterin, to serving as a processivity factor for telomerase during telomere extension.

PP2A and Aurora differentially modify Cdc13 to promote telomerase release from telomeres at G2/M phase

“…Consistently, ataxia telangiectasia mutated (ATM)/ATM-and Rad3-related (ATR)-promoted Ccq1-Est1 interaction was recently revealed 51 . It will be interesting to know whether ATM/ATR promotes the TPP1-POT1 complex-mediated telomerase recruitment in mammals 52,53 as observed in yeasts.…”

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.…”

Replication of Telomeres and the Regulation of Telomerase

“…The single-stranded telomere-binding protein Pot1 is an inhibitor of telomerase per se when binding to the 3 0 end of the substrate (Kelleher et al 2005;Lei et al 2005). When associated with Tpp1, however, Pot1 -Tpp1 decreases the dissociation of primer from telomerase and increases the efficiency of translocation (Wang et al 2007;Latrick and Cech 2010). Therefore, the Pot1 -Tpp1 complex increases repeat addition processivity of human telomerase severalfold.…”