ABSTRACT
As described in the preceding chapter, the cell can mobilize extensive resources to repair DNA damage. For the effective exploitation of these resources, the mechanism by which the damage is detected must be rapid, sensitive, and discriminate between multiple types of damage. Endogenous DNA damage occurs at high frequency with the loss of bases due to the spontaneous hydrolysis of DNA glycosyl bonds being of the order of 104 events per day per cell. At the same time, an array of physically dissimilar DNA lesions produced by exogenous insults must be distinguished from each other. Ultraviolet (UV) light induces dimerization of adjacent pyrimidines, photoproducts, and bulky DNA adducts creating obstacles to DNA transcription and replication, which are ultimately repaired by nucleotide excision repair (NER) proteins (Chapter 7). Ionizing radiation or the reactive oxygen intermediates produced as a consequence of oxidative metabolism cause DNAdouble-strand breaks (DSBs), which are repaired by homologous recombination or nonhomologous end-joining (NHEJ). Efficient detection of DNA damage is particularly important for dividing cells where replication or segregation of chromosomes bearing unrepaired lesions could seriously compromise genome integrity. The spectrum of DNA lesions is recognized by DNA-damage-response
pathways that transduce a signal from a damage sensor or detector to a series of downstream effector molecules via a sequence of events that is referred to as a signal-transduction cascade or pathway. This is initiated when the signal (DNA damage) is detected by a sensor (DNA-damage binding protein) triggering the activation of a transducer system (protein kinase cascade) that amplifies and diversifies the signal by targeting a series of downstream effectors of the DNA-damage response (shown schematically in Figure 8.1). This system is extremely sensitive and selective; it is triggered rapidly and efficiently by one or a few chromosomal DNA DSBs, while remaining inactive under other conditions.
