Studies of human cancer predisposition syndromes and mouse knockout models have revealed several connections between defects in DNA damage response and tumorigenesis. Several recently identified genes, includingATM(ataxia telangiectasia mutated),BRCA1, BRCA2, andNbs1(Nijmegen breakage syndrome gene), act as tumor suppressors by regulating various aspects of the cellular damage response pathway. In all of these cases, inactivating mutations cause defects in DNA damage signaling, giving rise to some form of chromosomal instability and predisposition to cancer. This chapter is concerned with the relationship between these tumor suppressors and the cellular DNA damage response, and focuses primarily on how defects in the tumor suppressor-dependent DNA damage signaling pathway may cause genetic instability, thereby facilitating tumorigenesis, and, in some cases, providing an opportunity for selective therapy.
