ReviewDNA damage responses to oxidative stress
Section snippets
The DNA damage response
Every cell in prokaryote or eukaryote is continuously exposed to exogenous and endogenous agents that damage its DNA. The many types of DNA lesions that result from these insults are rapidly detected, with subsequent activation of an intricate web of signaling pathways known as the DNA damage response. This response culminates in activation of cell-cycle checkpoints and the appropriate DNA repair pathways, or, in certain contexts, initiation of apoptotic programs. The DNA damage response is a
The ATM protein—a major transducer in the DNA damage response pathway
The ATM protein was identified as the product of the gene that is mutated in the human genetic disease ataxia-telangiectasia (A-T). A-T is characterized by progressive cerebellar degeneration, immunodeficiency, genome instability, premature aging, gonadal dysgenesis, extreme radiosensitivity, and high incidence of lymphoreticular malignancies (for review, see [22]). One of the most devastating symptoms of A-T—cerebellar ataxia—develops progressively into general motor dysfunction. Post-mortem
Oxidative stress
Cellular oxygen concentrations are maintained with a narrow “nomoxic” range to circumvent the risk of oxidative damage from excess O2 (hyperoxia) and of metabolic demise from insufficient O2 (hypoxia) [40]. pO2 ranges from 90 to bellow 3 Torr in mammalian organs under normoxic conditions with arterial pO2 of 100 Torr or ∼14% [41]. Thus, “normoxia” for cells is an adjustable variable that is dependent on the specific localization of the cell in organs and functional status of the specific tissue.
Loss of ATM leads to oxidative stress
Inactivation of a transducer that mediates the DNA damage response can lead to accumulation of DNA damage, loss of homeostasis and alterations in the cellular redox state. Perturbation of the cellular balance of ROS leading to constant oxidative stress is a common denominator of the genomic instability syndromes—disorders that reflect a defect in the DNA damage response. ATM deficiency is one of the most extensively studied of these disorders with regard to the connection between genome
The effect of oxidative stress on DNA repair
8-Hydroxydeoxyguanosine (8-OHdG), an oxidized form of guanine, is the major oxidative DNA-damage product that can produce mutations—A:T to C:C or G:C to T:A transversion mutations—because of its base pairing with adenine as well as cytosine (reviewed in [48]). It has been proposed that, unlike bulky DNA lesions, oxidized base lesions such as 8-OHdG and 5-hydroxyuracil are incorporated by DNA polymerases in the nascent DNA strand from the deoxynucleotide pool. Thus, 8-OHdG can be incorporated
The effect of oxidative stress on cell cycle checkpoint pathways
Proliferative mammalian cells exhibit a broad spectrum of responses to oxidative stress, depending on the level of the stress. A very low level of hydrogen peroxide (∼10 μM) causes a significant mitrogenic response. Greater concentrations of hydrogen peroxide (∼150 μM) lead to a temporary growth arrest state in which DNA is protected by histone proteins, energy is conserved by diminished expression of nonessential genes, and the expression of shock and stress proteins is greatly increased. At
Conclusions
Controlling the cellular redox state is a highly complex process governed by a myriad of cellular factors and systems. To maintain redox homeostasis, aerobic cells have developed elaborate detection devices that sense alterations in the levels of different kinds of ROS and activate an intricate network to neutralize them and repair the damage. The obvious solution to many oxidative-related damage states is to exogenously add antioxidants. But, cellular homeostasis is an extremely delicate
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