The cellular control of DNA double-strand breaks

The DSB is probably the most dangerous of the many types of DNA damage that exist within the cell. They arise from exogenous agents such as ionizing radiation (IR) and certain chemotherapeutic drugs, from endogenously generated reactive oxygen species and from chromosomal stress. A DNA replication fork that encounters DNA single-strand breaks or other types of lesion will also produce DSBs. They can occur at the ends of chromosomes due to defective metabolism of telomeres [Pandita, 2002a,b]. In addition, DNA DSBs can also form in a programmed manner during development. They are generated to initiate recombination between homologous chromosomes during meiosis and occur as intermediates during developmentally regulated rearrangements, such as V(D)J recombination and immunoglobulin class-switch recombination. The inability to respond properly to, or to repair, DNA DSBs has the potential to lead to genomic instability, which in turn may either lead to cell death or increase the risk of pathological consequences such as cancer development. The repair of DNA DSBs must occur in the context of chromatin, and there is increasing evidence that the modulation of chromatin plays an integral role in the DNA DSB repair process. It is becoming evident that a defect in the signaling and repair of DSBs is instrumental in the development of a number of human cancers. There are also a number of human disorders, which are characterized by defects in proteins that function in the control of DSBs. The study of these disorders has provided enormous insight into the cellular control of DSBs.