DNA-binding determinants and cellular thresholds for human telomerase repeat addition processivity

The EMBO Journal
Robert Alexander WuKathleen Collins

Abstract

The reverse transcriptase telomerase adds telomeric repeats to chromosome ends. Purified human telomerase catalyzes processive repeat synthesis, which could restore the full ~100 nucleotides of (T2AG3)n lost from replicated chromosome ends as a single elongation event. Processivity inhibition is proposed to be a basis of human disease, but the impacts of different levels of processivity on telomere maintenance have not been examined. Here, we delineate side chains in the telomerase active-site cavity important for repeat addition processivity, determine how they contribute to duplex and single-stranded DNA handling, and test the cellular consequences of partial or complete loss of repeat addition processivity for telomere maintenance. Biochemical findings oblige a new model for DNA and RNA handling dynamics in processive repeat synthesis. Biological analyses implicate repeat addition processivity as essential for telomerase function. However, telomeres can be maintained by telomerases with lower than wild-type processivity. Furthermore, telomerases with low processivity dramatically elongate telomeres when overexpressed. These studies reveal distinct consequences of changes in telomerase repeat addition processivity and express...Continue Reading

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Citations

Jan 20, 2018·International Journal of Molecular Sciences·Aina Bernal, Laura Tusell
Jan 3, 2018·Nucleic Acids Research·Olga A PetrovaVladimir I Polshakov
Feb 2, 2018·Molecular Biology of the Cell·Jens C SchmidtThomas R Cech
Feb 15, 2018·The EMBO Journal·Yinnan ChenJulian J-L Chen
Mar 4, 2020·Cancers·Nalini SrinivasRajiv Kumar
Aug 28, 2019·Cold Spring Harbor Perspectives in Biology·Yaqiang WangJuli Feigon
Feb 19, 2020·Nature Chemical Biology·Eric M PatrickJens C Schmidt
Apr 26, 2019·Proceedings of the National Academy of Sciences of the United States of America·Linnea I JanssonMichael D Stone
Jul 22, 2017·Current Opinion in Structural Biology·Yaqiang Wang, Juli Feigon
Apr 23, 2021·Nature·George E GhanimThi Hoang Duong Nguyen
Jul 21, 2021·Proceedings of the National Academy of Sciences of the United States of America·Ranjodh SandhuLifeng Xu

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