Each of the ~1013
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 reactive-oxygen compounds arising as byproducts from oxidative respiration or through redox-cycling 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 provided by the aftermaths of the Chernobyl nuclear-reactor disaster and nuclear detonations over Japan in World War II.
Today, probably the most prevalent environmental cancer-causing chemicals are those produced by tobacco products, which trigger various cancers, most notably those of the lung, oral cavity and adjacent tissues6, 7
. Cancer-causing DNA-damaging chemicals can also contaminate foods, such as aflatoxins found in contaminated peanuts and heterocyclic amines in over-cooked meats7
. DNA-damaging chemicals have also been used in warfare, and on a more positive note, are widely used to treat cancer8
and ailments such as psoriasis9
Here, we describe how DNA lesions are dealt with at the molecular level. We then explain how such responses affect many cellular processes, their biological significance and their roles in preventing human diseases. Finally, we illustrate how our increasing knowledge of DNA-damage responses is providing opportunities for improving disease detection and management.