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PMID:16043710

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Citation

Zaug, AJ, Podell, ER and Cech, TR (2005) Human POT1 disrupts telomeric G-quadruplexes allowing telomerase extension in vitro. Proc. Natl. Acad. Sci. U.S.A. 102:10864-9

Abstract

The POT1 (protection of telomeres 1) protein binds the ssDNA overhangs at the ends of chromosomes in diverse eukaryotes. POT1 is essential for chromosome end-protection, as best demonstrated in fission yeast. In human cells, hPOT1 is also involved in telomere-length regulation. We now show that telomeric oligonucleotides, such as d[GGG(TTAGGG)(3)], which form intramolecular G-quadruplexes through Hoogsteen base-pairing, serve as only marginal primers for extension by recombinant human telomerase; telomerase stalls after every nucleotide addition. Addition of hPOT1 to the reaction restores the normal processive elongation pattern seen with primers that cannot form G-quadruplexes. hPOT1 does not act catalytically but, instead, forms a stoichiometric complex with the DNA, freeing its 3' tail. An antisense oligonucleotide, which base-pairs near the 5' end of the telomeric sequence, leaving a telomerase-extendable 3' tail, duplicates the effect of hPOT1 on activation of G-quadruplex primers. Thus, hPOT1 may function simply by trapping the unfolded forms of these telomeric primers in an equilibrium population. We propose an additional role for hPOT1 in telomere maintenance: disrupting G-quadruplex structures in telomeric DNA, thereby allowing proper elongation by telomerase.

Links

PubMed PMC1180509 Online version:10.1073/pnas.0504744102

Keywords

Base Sequence; DNA/chemistry; DNA/genetics; DNA/metabolism; DNA Primers/genetics; DNA-Binding Proteins/genetics; DNA-Binding Proteins/metabolism; Humans; Macromolecular Substances; Models, Biological; Nucleic Acid Conformation; Recombinant Proteins/genetics; Recombinant Proteins/metabolism; Telomerase/genetics; Telomerase/metabolism; Telomere/metabolism; Telomere-Binding Proteins/genetics; Telomere-Binding Proteins/metabolism

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:TERT

involved_in

GO:0007004: telomere maintenance via telomerase

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:TERT

involved_in

GO:0022616: DNA strand elongation

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:TERT

enables

GO:0003720: telomerase activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:POTE1

involved_in

GO:0032202: telomere assembly

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:POTE1

involved_in

GO:0051973: positive regulation of telomerase activity

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:POTE1

involved_in

GO:0060383: positive regulation of DNA strand elongation

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete


See also

References

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