The DNA-damage response in human biology and disease

Abstract

The prime objective for every life-form is to deliver its genetic material, intact and unchanged, to the next generation. This must be achieved despite constant assaults by endogenous and environmental agents on the DNA. To counter this threat, life has evolved several systems to detect DNA damage, signal its presence and mediate its repair. Such responses, which impact a wide range of cellular events, are biologically significant because they prevent diverse human diseases. Our improving understanding of DNA-damage responses is providing new avenues for disease management.Each of the ~10 13 cells in the human body receives tens of thousands of DNA lesions per day1. These lesions can block genome replication and transcription, and if they are not repaired or are repaired incorrectly, they lead to mutations or wider-scale genome aberrations that threaten cell or organism viability. Some DNA aberrations arise via physiological processes, such as DNA mismatches occasionally introduced during DNA replication and DNA strand breaks caused by abortive topoisomerase I and topoisomerase II activity. In addition, hydrolytic reactions and non-enzymatic methylations generate thousands of DNA-base lesions per cell per day. DNA damage is also produced by reactiveoxygen compounds arising as byproducts from oxidative respiration or through redoxcycling events involving environmental toxins and Fenton reactions mediated by heavy metals2. Reactive oxygen and nitrogen compounds are also produced by macrophages and neutrophils at sites of inflammation and infections3. Such chemicals can attack DNA, leading to adducts that impair base-pairing and/or block DNA replication and transcription, base loss, or DNA single-strand breaks (SSBs). Furthermore, when two SSBs arise in close proximity, or when the DNA-replication apparatus encounters a SSB or certain other lesions, double-strand breaks (DSBs) are formed. While DSBs do not occur as frequently as the other lesions listed above, they are difficult to repair and extremely toxic4.The most pervasive environmental DNA-damaging agent is ultraviolet light (UV). While the ozone layer absorbs the most dangerous part of the solar UV spectrum (UV-C), residual UV-A and UV-B in strong sunlight can induce ~100,000 lesions per exposed cell per hour. Ionizing radiation (IR) also generates various forms of DNA damage, the most toxic of these being DSBs5. Some IR results from radioactive decay of naturally-occurring radioactive compounds. For example, uranium decay produces radioactive radon gas that accumulates in some homes and contributes to lung-cancer incidence. Exposure to natural or man-made radioisotopes also occurs during cancer radiotherapy, while the radioactive compounds iodine-131 and technetium-99m are exploited to diagnose and treat benign and malignant thyroid diseases. Lessons about the health consequences of excessive radiation exposure are Today, probably the most prevalent environmental cancer-causing chemicals are those produced by tobacco products, which trigger various ...

Germ Cell Apoptosis and DNA Damage Responses

“…In the context of the germline, transposon activity, which results in transient DNA double-strand breakage, equally has to be dealt with. In response to DNA damage, cells activate DNA damage response pathways that will coordinate various DNA repair pathways best suited to repair speci fi c lesions (for review, see Jackson and Bartek 2009 ) . At the same time DNA damage response pathways lead to a transient cell cycle arrest, in order to allow for DNA repair before mutations might be fi xed.…”

The nucleoporin 153, a novel factor in double-strand break repair and DNA damage response

“…1 DSBs can be repaired by one of two major pathways: homology-based repair (homologous recombination (HR)) using the intact chromatid as a template present in proximity in S and G2 phases of the cell cycle, or direct joining across the break site (non-homologous end joining (NHEJ)). 2 The coordination between cell cycle progression and DSB repair (DSBR) is regulated by the DNA damage response (DDR) signalling pathway, which activates the cell cycle checkpoints in the presence of DNA breaks.…”

G 2 /M cell cycle arrest on HT-29 cancer cells and toxicity assessment of triphenylphosphanegold(I) carbonimidothioates, Ph 3 PAu[SC(OR) = NPh], R = Me, Et, and iPr, during zebrafish development

“…In the cell cycle checkpoint signaling cascade, mediators provide a platform for signal transduction, activated transducers, DNA damage sensors, and their effectors leading to cell cycle arrest and other necessary metabolic actions [11]. Eukaryotic cell cycle checkpoints are responsible for the regulation of sequential formation, activation, and subsequent inactivation of cyclin dependent kinases, the activation of which is dependent upon an association with cyclins [12].…”

“…Eukaryotic cell cycle checkpoints are responsible for the regulation of sequential formation, activation, and subsequent inactivation of cyclin dependent kinases, the activation of which is dependent upon an association with cyclins [12]. Therefore, failing to maintain genomic integrity results in accretion of multiple deleterious mutations and may lead to cancer development [11]. Furthermore, deregulation of the cell cycle resulting in uncontrolled cell proliferation, is one of the most common alterations that occurs during tumor development [13].…”