Oncogenic activation of RAS, AKT and other growth signaling pathways induces reactive oxygen species (ROS) and DNA replication stress, both of which cause DNA damage and senescence at early stages of cancer. In cultured human cells, high concentrations of glucose that mimic the effects of hyperglycemia also activate AKT signaling and induce ROS, DNA damage and senescence. Chronic hyperglycemia associated with diabetes and high carbohydrate diets is a risk factor for cancer and likely contributes to aging in humans.
My laboratory is investigating how DNA damage and cellular senescence arise downstream of the sustained activation of growth signaling by glucose and whether DNA damage induced by high glucose contributes to cancer. DNA damage and senescence that depends on AKT signaling are also induced by glucose in the model organism S. cerevisiae (budding yeast) in parallel with a shorter chronological lifespan. We recently reported that in addition to inducing elevated ROS, activation of RAS and AKT pathways by glucose in S. cerevisiae triggers replication stress and DNA damage in cells in stationary phase1-3. Both replication stress and oxidative stress induced by glucose may contribute to the chronological age-dependent activation of retrotransposons in S. cerevisiae recently discovered by others in collaboration with our laboratory4. Our laboratory and collaborators in Portugal have also determined that caloric restriction imposed by reducing the concentration of glucose extends the chronological lifespan of S. cerevisiae by reducing intracellular levels of one form of ROS – superoxide anions – via a hormesis-like mechanism that triggers elevated levels of a different form of ROS (hydrogen peroxide), which activates superoxide dismutases5. We are investigating potential connections between these findings and the first NADPH oxidase discovered recently in S. cerevisiae in a collaboration between our laboratory and several laboratories in Europe6. We also recently established that caloric restriction attenuates replication stress, in addition to attenuating oxidative stress, and that replication stress induces oxidative stress in the form of superoxide anions3. Superoxide anions also inhibit exit from S phase in stationary phase, thus inducing replication stress2,6. The complex interplay between oxidative stress and replication stress revealed by these studies points to the existence of regulatory loops triggered by glucose signaling or oncogene activation that amplify both oxidative and replication stress (Fig. 1).
In addition to an elevated risk of developing cancer, patients with diabetes also exhibit elevated sister chromatid exchanges, which are initiated at damaged replication forks. Current efforts in our laboratory are focused on determining whether chronic hyperglycemia induces replication stress and DNA damage in specific regions of human chromosomes that are frequently mutated in tumors. Glucose-induced replication stress and DNA damage could represent a previously unknown link between cancer and aging and high carbohydrate western diets.
Fig. 1. Complex interplay between oxidative stress and DNA replication stress induced by glucose signaling in the model organism S. cerevisiae. Sustained growth signaling by glucose triggers increased intracellular levels of superoxide anions and induces DNA replication stress. In addition to inducing DNA damage and senescence directly, DNA replication stress also elevates levels of superoxide anions. Conversely, superoxide anions can trap stationary phase cells in S phase, where they undergo replication stress. Increased superoxide anions associated with replication stress could cause the activation of regulatory loops that amplify replication stress and oxidative stress, and thus DNA damage and senescence. Mutations that constitutively activate glucose signaling pathways could also amplify these events. According to this model, caloric restriction promotes longevity by inhibiting senescence induced by both oxidative and replication stress. Similar mechanisms may promote health and longevity in humans and other complex organisms.
- DNA replication, checkpoints and apoptosis
- DNA replication stress, cancer and aging
- Gene silencing and genome evolution
Burhans W, Weinberger M. Yeast endonuclease G: complex matters of death, and of life. Molecular Cell 2007; 25(3): 323-325.
Burhans W, Weinberger M. DNA replication stress, genome instability and aging. Nucleic Acids Research 2007; 35(22): 7545-7556.
Maslov AY, Bailey KJ, Mielnicki LM, Freeland A, Sun X, Burhans W, Pruitt S. Stem/progenitor cell-specific enhanced green fluorescent protein expression driven by the endogenous Mcm2 promoter. Stem Cells 2007; 25(1): 132-138.
Weinberger M, Feng L, Paul A, Smith DL Jr, Hontz RD, Smith JS, Vujcic M, Singh K, Huberman J, Burhans W. DNA replication stress is a determinant of chronological lifespan in budding yeast. PLoS One 2007; 2(8): e748.
Rinnerthaler M, Heeren G, Laun P, Koessler S, Rid R, Klinger H, Weinberger M, Burhans W, Breitenbach M. The role of a yeast NAD(P)H-oxidase in aging and apoptosis. Free Radical Research 2008; 42(Suppl. 1): S99.
Madia F, Gattazzo C, Wei M, Fabrizio P, Burhans W, Weinberger M, Galbani A, Smith JR, Nguyen C, Huey S, Comai L, Longo VD. Longevity mutation in SCH9 prevents recombination errors and premature genomic instability in a Werner/Bloom model system. Journal of Cell Biology 2008; 180(1): 67-81.
Burhans W, Heintz NH. The cell cycle is a redox cycle: linking phase-specific targets to cell fate. Free Radical Biology and Medicine 2009; 47(9): 1282-1293.
Burhans W, Weinberger M. Acetic acid effects on aging in budding yeast: are they relevant to aging in higher eukaryotes?. Cell Cycle 2009; 8(14): 2300-2302.
Mesquita A, Weinberger M, Silva A, Sampaio-Marques B, Almeida B, Leao C, Costa V, Rodrigues F, *Burhans W, *Ludovico P. Caloric restriction or catalase inactivation extends yeast chronological lifespan by inducing H2O2 and superoxide dismutase activity. Proceedings of the National Academy of Sciences of the United States of America 2010; 107(34): 15123-15128. *(co-corresponding authors)
Burhans W, Weinberger M. Revisiting the free radical theory using next-generation sequencing technology. Aging (Albany NY) 2010; 2(8): 459-460.
Burhans W, Weinberger M. Histone genes, DNA replication, apoptosis and aging: what are the connections?. Cell Cycle 2010; 9(20): 4047-4048.
Weinberger M, Mesquita A , Carroll T , Marks L , Yang H , Zhang ZJ , Ludovico P , Burhans W. Growth signaling promotes chronological aging in budding yeast by inducing superoxide anions that inhibit quiescence. Aging (Albany NY) 2010; 2(10): 709-726.
Burhans W, Weinberger M. DNA Damage and DNA Replication Stress in Yeast Models of Aging. Sub-cellular Biochemistry 2012; 57( ): 187-206.
Maxwell PH, Burhans W, Curcio MJ. Retrotransposition is associated with genome instability during chronological aging.Proceedings of the National Academy of Sciences of the United States of America 2011; 108(51): 20376-20381.
Rinnerthaler M, Buttner S, Laun P, Heeren G, Felder TK, Klinger H, Weinberger M, Stolze K, Grousl T, Hasek J, Benada O, Frydlova I, Klocker A, Simon-Nobbe B, Jansko B, Breitenbach-Koller H, Eisenberg T, Gourlay CW, Madeo F, *Burhans W, *Breitenbach M. Yno1p/Aim14p, a NADPH-oxidase ortholog, controls extramitochondrial reactive oxygen species generation, apoptosis, and actin cable formation in yeast. Proceedings of the National Academy of Sciences of the United States of America 2012; 109(22): 8658-8663. *(co-corresponding authors)
Laun P, Buttner S, Rinnerthaler M, Burhans W, Breitenbach M. Yeast aging and apoptosis. Sub-cellular Biochemistry 2012; 57( ): 207-232.
Ludovico P, Osiewacz HD, Costa V, Burhans W. Cellular models of aging. Oxidative Medicine and Cellular Longevity 2012; 2012( ): 616128.
Moparthy S, Moparthy K, Wheeler LJ, Natarajan V, Zucker S, Fink E, Im M, Flanagan S, Burhans W, Zeitouni N, Shewach DS, Mathews CK, Nikiforov M. Depletion of deoxyribonucleotide pools is an endogenous source of DNA damage in cells undergoing oncogene-induced senescence. American Journal of Pathology 2013; 182(1): 142-151.
Weinberger M, Sampaio-Marques B, Ludovico P, Burhans W. (2013). DNA replication stress-induced loss of reproductive capacity in S. cerevisiae and its inhibition by caloric restriction. Cell Cycle 12, 1189-1200.