title: 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.
authors.affiliation: Department of Biological Chemistry, University of Michigan Medical School, MSRBIII 5301D, 1150 W. Medical Center Drive, Ann Arbor, Michigan 48109, USA.
authors.forename: Feng
authors.initials: F
authors.lastname: Wang
authors.forename: Elaine R
authors.initials: ER
authors.lastname: Podell
authors.forename: Arthur J
authors.initials: AJ
authors.lastname: Zaug
authors.forename: Yuting
authors.initials: Y
authors.lastname: Yang
authors.forename: Paul
authors.initials: P
authors.lastname: Baciu
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Cech
authors.forename: Ming
authors.initials: M
authors.lastname: Lei
mesh_terms: D018360:Crystallography, X-Ray; D004277:DNA, Single-Stranded / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D006801:Humans; D046912:Multiprotein Complexes / Q000737:chemistry / Q000378:metabolism; D009690:Nucleic Acid Conformation; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D021122:Protein Subunits / Q000737:chemistry / Q000378:metabolism; D000089804:Shelterin Complex; D040681:Structural Homology, Protein; D019098:Telomerase / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism*; D034501:Telomere-Binding Proteins / Q000737:chemistry* / Q000378:metabolism*
chemical_list: C495876:ACD protein, human; D004277:DNA, Single-Stranded; D046912:Multiprotein Complexes; C440849:POT1 protein, human; D021122:Protein Subunits; D000089804:Shelterin Complex; D034501:Telomere-Binding Proteins; D019098:Telomerase