Rnr1, but not Rnr3, facilitates the sustained telomerase-dependent elongation of telomeres

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.

Gazy, Inbal (author)
Sharma, SushmaUmeå universitet,Institutionen för medicinsk kemi och biofysik,Andrei Chabes(Swepub:umu)sush0003 (author)
Marjavaara, LisetteUmeå universitet,Institutionen för medicinsk kemi och biofysik,Andrei Chabes(Swepub:umu)lietoa93 (author)
Grinberg, Gilad (author)
Shemesh, Keren (author)
Chabes, AndreiUmeå universitet,Institutionen för medicinsk kemi och biofysik,Molekylär Infektionsmedicin, Sverige (MIMS)(Swepub:umu)anch0002 (author)
Kupiec, Martin (author)
Umeå universitetInstitutionen för medicinsk kemi och biofysik (creator_code:org_t)

By the author/editor: Maicher, André; Gazy, Inbal; Sharma, Sushma; Marjavaara, Lise ...; Grinberg, Gilad; Shemesh, Keren; show more...; Chabes, Andrei; Kupiec, Martin; show less...

About the subject

NATURAL SCIENCES: NATURAL SCIENCES; and Biological Scien ...; and Biochemistry and ...

MEDICAL AND HEALTH SCIENCES: MEDICAL AND HEAL ...; and Basic Medicine; and Other Basic Medi ...

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