Function and Regulation of Yeast Ribonucleotide Reductase: Cell Cycle, Genotoxic Stress, and Iron Bioavailability

Puig, Sergi; Sanvisens, Nerea; Llanos, Rosa De

Abstract

All eukaryotic organisms require an adequate, balanced concentration of deoxyribonucleoside triphosphates (dNTPs) in order to assure accurate DNA replication and repair, and to maintain genomic integrity. The rate‑limiting step in dNTP synthesis is catalyzed by ribonucleotide reductase (RNR), an essential enzyme mediating the reduction of ribonucleotides to desoxyribonucleotides, thereby providing the building blocks required for DNA synthesis. Consistent with its important role in cell proliferation, a significant increase in RNR activity has been associated with tumor cells and resistance to chemotherapy. Indeed, since the utilization of hydroxyurea in the 70s to the current development of sophisticated RNR inhibitors, RNR as been used as an important target for the chemotherapeutic treat‑ ment of numerous cancer types. [1] Therefore, understanding the molecular mechanisms that cells utilize to regulate RNR function in response to different stresses is critical for the development of new and efficient anticancer therapies. In this review, we focus on the yeast S. cerevisiae as a eukaryotic model to advance in our understanding of mechanisms regulating the function of eukaryotic RNRs during cell cycle progress and in response to environmental cues, including genotoxic stress and low iron bioavailability. RNR structure, assembly, and allosteric regulation In eukaryotes, class Ia RNRs are oxygen‑dependent enzymes composed of a large R1 (α 2) and a small R2 (β 2 or ββ′) subunit. The R1 subunit contains the catalytic site and two allosteric effector binding sites that Review Article Ribonucleotide reductases (RNRs) are essential enzymes that catalyze the reduction of ribonucleotides to desoxyribonucleotides, thereby providing the building blocks required for de novo DNA biosynthesis. The RNR function is tightly regulated because an unbalanced or excessive supply of deoxyribonucleoside triphosphates (dNTPs) dramatically increases the mutation rates during DNA replication and repair that can lead to cell death or genetic anomalies. In this review, we focus on Saccharomyces cerevisiae class Ia RNR as a model to understand the different mechanisms controlling RNR function and regulation in eukaryotes. Many studies have contributed to our current understanding of RNR allosteric regulation and, more recently, to its link to RNR oligomerization. Cells have developed additional mechanisms that restrict RNR activity to particular periods when dNTPs are necessary, such as the S phase or upon genotoxic stress. These regulatory strategies include the transcriptional control of the RNR gene expression, inhibition of RNR catalytic activity, and the subcellular redistribution of RNR subunits. Despite class Ia RNRs requiring iron as an essential cofactor for catalysis, little is known about RNR function regulation depending on iron bioavailability. Recent studies into yeast have deciphered novel strategies for the delivery of iron to RNR and for its regulation in response to iron deficiency. Taken together, these studies open up new possibilities to explore in order to limit uncontrolled tumor cell proliferation via RNR.

Citation

Puig, S., Sanvisens, N., & Llanos, R. D. (2013). Function and Regulation of Yeast Ribonucleotide Reductase: Cell Cycle, Genotoxic Stress, and Iron Bioavailability. Biomedical Journal, 36(2), https://doi.org/10.4103/2319-4170.110398

• Journal Article Type: Article
• Acceptance Date: Oct 5, 2012
• Publication Date: Mar 1, 2013
• Deposit Date: Sep 22, 2016
• Publicly Available Date: Sep 22, 2016
• Journal: Biomedical Journal
• Print ISSN: 2319-4170
• Publisher: Chang Gung University
• Peer Reviewed: Peer Reviewed
• Volume: 36
• Issue: 2
• DOI: https://doi.org/10.4103/2319-4170.110398
• Keywords: cell cycle; genotoxic stress; iron deficiency; ribonucleotide reductase; Saccharomyces cerevisiae; yeast
• Public URL: http://researchrepository.napier.ac.uk/Output/388130