The POT1-TPP1 telomere complex is a telomerase processivity factor.
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.
Wang
Feng
F
Department of Biological Chemistry, University of Michigan Medical School, MSRBIII 5301D, 1150 W. Medical Center Drive, Ann Arbor, Michigan 48109, USA.
Podell
Elaine R
ER
Zaug
Arthur J
AJ
Yang
Yuting
Y
Baciu
Paul
P
Cech
Thomas R
TR
Lei
Ming
M
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*
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