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Rnr1, but not Rnr3, facilitates the sustained telomerase-dependent elongation of telomeres
Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics. (Andrei Chabes)
Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics. (Andrei Chabes)
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2017 (English)In: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 13, no 10, article id e1007082Article in journal (Refereed) Published
Abstract [en]

Ribonucleotide reductase (RNR) provides the precursors for the generation of dNTPs, which are required for DNA synthesis and repair. Here, we investigated the function of the major RNR subunits Rnr1 and Rnr3 in telomere elongation in budding yeast. We show that Rnr1 is essential for the sustained elongation of short telomeres by telomerase. In the absence of Rnr1, cells harbor very short, but functional, telomeres, which cannot become elongated by increased telomerase activity or by tethering of telomerase to telomeres. Furthermore, we demonstrate that Rnr1 function is critical to prevent an early onset of replicative senescence and premature survivor formation in telomerase-negative cells but dispensable for telomere elongation by Homology-Directed-Repair. Our results suggest that telomerase has a "basal activity" mode that is sufficient to compensate for the "end-replication-problem" and does not require the presence of Rnr1 and a different "sustained activity" mode necessary for the elongation of short telomeres, which requires an upregulation of dNTP levels and dGTP ratios specifically through Rnr1 function. By analyzing telomere length and dNTP levels in different mutants showing changes in RNR complex composition and activity we provide evidence that the Mec1ATR checkpoint protein promotes telomere elongation by increasing both dNTP levels and dGTP ratios through Rnr1 upregulation in a mechanism that cannot be replaced by its homolog Rnr3.

Place, publisher, year, edition, pages
2017. Vol. 13, no 10, article id e1007082
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Biochemistry and Molecular Biology Other Basic Medicine
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URN: urn:nbn:se:umu:diva-141579DOI: 10.1371/journal.pgen.1007082ISI: 000414161300038PubMedID: 29069086OAI: oai:DiVA.org:umu-141579DiVA, id: diva2:1155532
Available from: 2017-11-08 Created: 2017-11-08 Last updated: 2018-06-09Bibliographically approved

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Maicher, AndréSharma, SushmaMarjavaara, LisetteChabes, Andrei
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