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 ...

During the evolution of cancer, the incipient tumour experiences 'oncogenic stress', which evokes a counter-response to eliminate such hazardous cells. However, the nature of this stress remains elusive, as does the inducible anti-cancer barrier that elicits growth arrest or cell death. Here we show that in clinical specimens from different stages of human tumours of the urinary bladder, breast, lung and colon, the early precursor lesions (but not normal tissues) commonly express markers of an activated DNA damage response. These include phosphorylated kinases ATM and Chk2, and phosphorylated histone H2AX and p53. Similar checkpoint responses were induced in cultured cells upon expression of different oncogenes that deregulate DNA replication. Together with genetic analyses, including a genome-wide assessment of allelic imbalances, our data indicate that early in tumorigenesis (before genomic instability and malignant conversion), human cells activate an ATR/ATM-regulated DNA damage response network that delays or prevents cancer. Mutations compromising this checkpoint, including defects in the ATM-Chk2-p53 pathway, might allow cell proliferation, survival, increased genomic instability and tumour progression.

All life on earth must cope with constant exposure to DNA-damaging agents such as the Sun's radiation. Highly conserved DNA-repair and cell-cycle checkpoint pathways allow cells to deal with both endogenous and exogenous sources of DNA damage. How much an individual is exposed to these agents and how their cells respond to DNA damage are critical determinants of whether that individual will develop cancer. These cellular responses are also important for determining toxicities and responses to current cancer therapies, most of which target the DNA.

Recent studies have indicated the existence of tumorigenesis barriers that slow or inhibit the progression of preneoplastic lesions to neoplasia. One such barrier involves DNA replication stress, which leads to activation of the DNA damage checkpoint and thereby to apoptosis or cell cycle arrest, whereas a second barrier is mediated by oncogene-induced senescence. The relationship between these two barriers, if any, has not been elucidated. Here we show that oncogene-induced senescence is associated with signs of DNA replication stress, including prematurely terminated DNA replication forks and DNA double-strand breaks. Inhibiting the DNA double-strand break response kinase ataxia telangiectasia mutated (ATM) suppressed the induction of senescence and in a mouse model led to increased tumour size and invasiveness. Analysis of human precancerous lesions further indicated that DNA damage and senescence markers cosegregate closely. Thus, senescence in human preneoplastic lesions is a manifestation of oncogene-induced DNA replication stress and, together with apoptosis, provides a barrier to malignant progression.