CiteWeb id: 20090000230

CiteWeb score: 2857

DOI: 10.1038/nature08467

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 day 1 . 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 infections 3 . Such chemicals can attack DNA,