This is a fascinating review by Jackson and Bartekon the DNA-damage response in human biology and disease in Nature .
Tens of thousands of DNA in each of the 1013 cells in the human body is damaged each day. 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 through 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 by-products from oxidative respiration or through redox-cycling events involving environmental toxic agents and Fenton reactions mediated by heavy metals. Reactive oxygen and nitrogen compounds are also produced by macrophages and neutrophils at sites of inflammation and infections. 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. Furthermore, when two single-strand breaks s arise in close proximity, or when the DNA-replication apparatus encounters a single-strand breaks or certain other lesions, double-strand breaks single-strand breaks are formed. Although double-strand breaks do not occur as frequently as the other lesions listed above, they are difficult to repair and extremely toxic.
The most pervasive environmental DNA-damaging agent is ultraviolet light. Although the ozone layer absorbs the most dangerous part of the solar ultraviolet spectrum (ultraviolet C), residual ultraviolet A and ultraviolet B in strong sunlight can induce -100,000 lesions per exposed cell per hour. Ionizing radiation also generates various forms of DNA damage, the most toxic of these being double-strand breaks. Some ionizing radiation 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 manmade radioisotopes also occurs during cancer radiotherapy, whereas 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 the Second World War.
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 tissues. Cancer-causing DNA-damaging chemicals can also contaminate foods, such as aflatoxins found in contaminated peanuts and heterocyclic amines in over-cooked meats. DNA-damaging chemicals have also been used in warfare, and on a more positive note, are widely used to treat cancers and ailments such as psoriasis.
They describe how DNA lesions are dealt with at the molecular level. The presence of a lesion in the DNA, which has consequences for replication is recognised by various sensor proteins. These proteins initiate many cellular processes, with biological significance which have roles in preventing human diseases. These include DNA repair pathways, DNA damage signalling and cell cycle checkpoints, a DNA damage response system.
Jackson and Bartek 2009 The DNA-damage response in human biology and disease Nature vol 461 pp 1071-78
- Martin Eastwood