Matches in SemOpenAlex for { <https://semopenalex.org/work/W2950201963> ?p ?o ?g. }
- W2950201963 endingPage "11596" @default.
- W2950201963 startingPage "11579" @default.
- W2950201963 abstract "Human telomerase maintains genome stability by adding telomeric repeats to the ends of linear chromosomes. Although previous studies have revealed profound insights into telomerase functions, the low cellular abundance of functional telomerase and the difficulties in quantifying its activity leave its thermodynamic and kinetic properties only partially characterized. Employing a stable cell line overexpressing both the human telomerase RNA component and the N-terminally biotinylated human telomerase reverse transcriptase and using a newly developed method to count individual extension products, we demonstrate here that human telomerase holoenzymes contain fast- and slow-acting catalytic sites. Surprisingly, both active sites became inactive after two consecutive rounds of catalysis, named single-run catalysis. The fast active sites turned off ∼40-fold quicker than the slow ones and exhibited higher affinities to DNA substrates. In a dimeric enzyme, the two active sites work in tandem, with the faster site functioning before the slower one, and in the monomeric enzyme, the active sites also perform single-run catalysis. Interestingly, inactive enzymes could be reactivated by intracellular telomerase-activating factors (iTAFs) from multiple cell types. We conclude that the single-run catalysis and the iTAF-triggered reactivation serve as an unprecedented control circuit for dynamic regulation of telomerase. They endow native telomerase holoenzymes with the ability to match their total number of active sites to the number of telomeres they extend. We propose that the exquisite kinetic control of telomerase activity may play important roles in both cell division and cell aging. Human telomerase maintains genome stability by adding telomeric repeats to the ends of linear chromosomes. Although previous studies have revealed profound insights into telomerase functions, the low cellular abundance of functional telomerase and the difficulties in quantifying its activity leave its thermodynamic and kinetic properties only partially characterized. Employing a stable cell line overexpressing both the human telomerase RNA component and the N-terminally biotinylated human telomerase reverse transcriptase and using a newly developed method to count individual extension products, we demonstrate here that human telomerase holoenzymes contain fast- and slow-acting catalytic sites. Surprisingly, both active sites became inactive after two consecutive rounds of catalysis, named single-run catalysis. The fast active sites turned off ∼40-fold quicker than the slow ones and exhibited higher affinities to DNA substrates. In a dimeric enzyme, the two active sites work in tandem, with the faster site functioning before the slower one, and in the monomeric enzyme, the active sites also perform single-run catalysis. Interestingly, inactive enzymes could be reactivated by intracellular telomerase-activating factors (iTAFs) from multiple cell types. We conclude that the single-run catalysis and the iTAF-triggered reactivation serve as an unprecedented control circuit for dynamic regulation of telomerase. They endow native telomerase holoenzymes with the ability to match their total number of active sites to the number of telomeres they extend. We propose that the exquisite kinetic control of telomerase activity may play important roles in both cell division and cell aging." @default.
- W2950201963 created "2019-06-27" @default.
- W2950201963 creator A5020028456 @default.
- W2950201963 creator A5052021355 @default.
- W2950201963 creator A5064673731 @default.
- W2950201963 creator A5071880594 @default.
- W2950201963 creator A5081012778 @default.
- W2950201963 creator A5088291121 @default.
- W2950201963 date "2019-07-01" @default.
- W2950201963 modified "2023-10-14" @default.
- W2950201963 title "Catalysis-dependent inactivation of human telomerase and its reactivation by intracellular telomerase-activating factors (iTAFs)" @default.
- W2950201963 cites W1579661837 @default.
- W2950201963 cites W1964393554 @default.
- W2950201963 cites W1970196890 @default.
- W2950201963 cites W1978002329 @default.
- W2950201963 cites W1979900842 @default.
- W2950201963 cites W1983856456 @default.
- W2950201963 cites W1989343323 @default.
- W2950201963 cites W1997685956 @default.
- W2950201963 cites W1998335196 @default.
- W2950201963 cites W2014013625 @default.
- W2950201963 cites W2014414194 @default.
- W2950201963 cites W2016324576 @default.
- W2950201963 cites W2016672919 @default.
- W2950201963 cites W2019549359 @default.
- W2950201963 cites W2026163223 @default.
- W2950201963 cites W2035898058 @default.
- W2950201963 cites W2042377388 @default.
- W2950201963 cites W2046909262 @default.
- W2950201963 cites W2049481441 @default.
- W2950201963 cites W2053556250 @default.
- W2950201963 cites W2053912477 @default.
- W2950201963 cites W2056916397 @default.
- W2950201963 cites W2057009728 @default.
- W2950201963 cites W2057953772 @default.
- W2950201963 cites W2062955305 @default.
- W2950201963 cites W2063257115 @default.
- W2950201963 cites W2069013139 @default.
- W2950201963 cites W2080045652 @default.
- W2950201963 cites W2080776393 @default.
- W2950201963 cites W2084804604 @default.
- W2950201963 cites W2086176257 @default.
- W2950201963 cites W2086429722 @default.
- W2950201963 cites W2091422977 @default.
- W2950201963 cites W2095811457 @default.
- W2950201963 cites W2099435547 @default.
- W2950201963 cites W2105948117 @default.
- W2950201963 cites W2113168077 @default.
- W2950201963 cites W2113618284 @default.
- W2950201963 cites W2114331456 @default.
- W2950201963 cites W2115099671 @default.
- W2950201963 cites W2124013587 @default.
- W2950201963 cites W2124242199 @default.
- W2950201963 cites W2126007886 @default.
- W2950201963 cites W2129920504 @default.
- W2950201963 cites W2132462187 @default.
- W2950201963 cites W2134283983 @default.
- W2950201963 cites W2138008248 @default.
- W2950201963 cites W2150490516 @default.
- W2950201963 cites W2152562488 @default.
- W2950201963 cites W2160185049 @default.
- W2950201963 cites W2160664302 @default.
- W2950201963 cites W2161355984 @default.
- W2950201963 cites W2161948433 @default.
- W2950201963 cites W2166024667 @default.
- W2950201963 cites W2194942599 @default.
- W2950201963 cites W2316035294 @default.
- W2950201963 cites W2394724717 @default.
- W2950201963 cites W2440582319 @default.
- W2950201963 cites W2550983084 @default.
- W2950201963 cites W2554540578 @default.
- W2950201963 cites W2592637707 @default.
- W2950201963 cites W2599022942 @default.
- W2950201963 cites W2799413964 @default.
- W2950201963 cites W2893463763 @default.
- W2950201963 cites W4210461863 @default.
- W2950201963 cites W4323966327 @default.
- W2950201963 doi "https://doi.org/10.1074/jbc.ra118.007234" @default.
- W2950201963 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/6663873" @default.
- W2950201963 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/31186347" @default.
- W2950201963 hasPublicationYear "2019" @default.
- W2950201963 type Work @default.
- W2950201963 sameAs 2950201963 @default.
- W2950201963 citedByCount "6" @default.
- W2950201963 countsByYear W29502019632020 @default.
- W2950201963 countsByYear W29502019632021 @default.
- W2950201963 countsByYear W29502019632022 @default.
- W2950201963 countsByYear W29502019632023 @default.
- W2950201963 crossrefType "journal-article" @default.
- W2950201963 hasAuthorship W2950201963A5020028456 @default.
- W2950201963 hasAuthorship W2950201963A5052021355 @default.
- W2950201963 hasAuthorship W2950201963A5064673731 @default.
- W2950201963 hasAuthorship W2950201963A5071880594 @default.
- W2950201963 hasAuthorship W2950201963A5081012778 @default.
- W2950201963 hasAuthorship W2950201963A5088291121 @default.
- W2950201963 hasBestOaLocation W29502019631 @default.
- W2950201963 hasConcept C104317684 @default.
- W2950201963 hasConcept C125593758 @default.