Survival of DNA damage in yeast directly depends on increased dNTP levels allowed by relaxed feedback inhibition of ribonucleotide reductase.
In eukaryotes, DNA damage elicits a multifaceted response that includes cell cycle arrest, transcriptional activation of DNA repair genes, and, in multicellular organisms, apoptosis. We demonstrate that in Saccharomyces cerevisiae, DNA damage leads to a 6- to 8-fold increase in dNTP levels. This increase is conferred by an unusual, relaxed dATP feedback inhibition of ribonucleotide reductase (RNR). Complete elimination of dATP feedback inhibition by mutation of the allosteric activity site in RNR results in 1.6-2 times higher dNTP pools under normal growth conditions, and the pools increase an additional 11- to 17-fold during DNA damage. The increase in dNTP pools dramatically improves survival following DNA damage, but at the same time leads to higher mutation rates. We propose that increased survival and mutation rates result from more efficient translesion DNA synthesis at elevated dNTP concentrations.
Chabes
Andrei
A
Department of Medical Biochemistry and Biophysics, Umeå University, SE 901 87 Umeå, Sweden. chabes@cshl.org
Georgieva
Bilyana
B
Domkin
Vladimir
V
Zhao
Xiaolan
X
Rothstein
Rodney
R
Thelander
Lars
L
D000255:Adenosine Triphosphate / Q000235:genetics / Q000378:metabolism; D001665:Binding Sites / Q000235:genetics; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics* / Q000528:radiation effects; D004247:DNA / Q000096:biosynthesis / Q000235:genetics; D004249:DNA Damage / Q000187:drug effects / Q000235:genetics* / Q000528:radiation effects; D004260:DNA Repair / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects; D003853:Deoxyribonucleosides / Q000235:genetics / Q000378:metabolism*; D005057:Eukaryotic Cells / Q000201:enzymology*; D025461:Feedback, Physiological / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects; D015966:Gene Expression Regulation, Fungal / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects; D009153:Mutagens / Q000494:pharmacology; D009154:Mutation / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects; D012264:Ribonucleotide Reductases / Q000235:genetics / Q000378:metabolism*; D012441:Saccharomyces cerevisiae / Q000201:enzymology* / Q000235:genetics*; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism
D003853:Deoxyribonucleosides; D009153:Mutagens; D029701:Saccharomyces cerevisiae Proteins; D000255:Adenosine Triphosphate; D004247:DNA; D012264:Ribonucleotide Reductases