Restriction of DNA replication to the reductive phase of the metabolic cycle protects genome integrity.

Department of Biochemistry, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA.
Science (Impact Factor: 31.48). 07/2007; 316(5833):1916-9. DOI: 10.1126/science.1140958
Source: PubMed

ABSTRACT When prototrophic yeast cells are cultured under nutrient-limited conditions that mimic growth in the wild, rather than in the high-glucose solutions used in most laboratory studies, they exhibit a robustly periodic metabolic cycle. Over a cycle of 4 to 5 hours, yeast cells rhythmically alternate between glycolysis and respiration. The cell division cycle is tightly constrained to the reductive phase of this yeast metabolic cycle, with DNA replication taking place only during the glycolytic phase. We show that cell cycle mutants impeded in metabolic cycle-directed restriction of cell division exhibit substantial increases in spontaneous mutation rate. In addition, disruption of the gene encoding a DNA checkpoint kinase that couples the cell division cycle to the circadian cycle abolishes synchrony of the metabolic and cell cycles. Thus, circadian, metabolic, and cell division cycles may be coordinated similarly as an evolutionarily conserved means of preserving genome integrity.

1 Follower
  • [Show abstract] [Hide abstract]
    ABSTRACT: Cell-autonomous circadian rhythms allow organisms to temporally orchestrate their internal state to anticipate and/or resonate with the external environment [1, 2]. Although ∼24-hr periodicity is observed across aerobic eukaryotes, the central mechanism has been hard to dissect because few simple models exist, and known clock proteins are not conserved across phylogenetic kingdoms [1, 3, 4]. In contrast, contributions to circadian rhythmicity made by a handful of post-translational mechanisms, such as phosphorylation of clock proteins by casein kinase 1 (CK1) and glycogen synthase kinase 3 (GSK3), appear conserved among phyla [3, 5]. These kinases have many other essential cellular functions and are better conserved in their contribution to timekeeping than any of the clock proteins they phosphorylate [6]. Rhythmic oscillations in cellular redox state are another universal feature of circadian timekeeping, e.g., over-oxidation cycles of abundant peroxiredoxin proteins [7-9]. Here, we use comparative chronobiology to distinguish fundamental clock mechanisms from species and/or tissue-specific adaptations and thereby identify features shared between circadian rhythms in mammalian cells and non-circadian temperature-compensated respiratory oscillations in budding yeast [10]. We find that both types of oscillations are coupled with the cell division cycle, exhibit period determination by CK1 and GSK3, and have peroxiredoxin over-oxidation cycles. We also explore how peroxiredoxins contribute to YROs. Our data point to common mechanisms underlying both YROs and circadian rhythms and suggest two interpretations: either certain biochemical systems are simply permissive for cellular oscillations (with frequencies from hours to days) or this commonality arose via divergence from an ancestral cellular clock. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.
    Current biology: CB 04/2015; DOI:10.1016/j.cub.2015.02.035 · 9.92 Impact Factor
  • Source
  • [Show abstract] [Hide abstract]
    ABSTRACT: We previously identified a mutation, smt15-1, that partially suppresses the cell cycle defects caused by loss of the retinoblastoma tumor suppressor related protein (RBR) encoded by the MAT3 gene in Chlamydomonas reinhardtii. smt15-1 single mutants were also found to have a cell cycle defect leading to a small-cell phenotype. SMT15 belongs to a previously uncharacterized sub-family of putative membrane localized sulfate/anion transporters that contain a Sulfate_transp domain and are found in a widely distributed subset of eukaryotes and bacteria. Although we observed that smt15-1 has a defect in acclimation to sulfur-limited growth conditions, sac mutants that are more severely defective for acclimation to sulfur limitation do not have cell cycle defects and cannot suppress mat3. Moreover, we found that smt15-1, but not sac mutants, over-accumulates glutathione. In wild-type cells glutathione fluctuated during the cell cycle with highest levels in mid-G1 phase and lower levels during S and M phases, while in smt15-1 glutathione levels remained elevated during S and M. In addition to increased total glutathione levels, smt15-1 cells had increased GSH/GSSH redox ratio throughout the cell cycle. These data suggest a role for SMT15 in maintaining glutathione homeostasis that impacts the cell cycle and sulfur acclimation responses.
    Plant physiology 10/2014; DOI:10.1104/pp.114.251009 · 7.39 Impact Factor