Multiple Signaling Pathways Involving ATM

Cellular responses to DNA damage have become central to the two major issues in the field of cancer biology:(1) How do cancers start and progress? (2) What determines the sensitivity of tumors to therapeutic interventions? Bacteria possess elaborate mechanisms to dealwith various types of DNA damage. In general, these response mechanisms appear to enhance survival and minimize genetic instability (unless the genetic instabilitywould enhance survival). Although many of the generalsteps involved have been relatively well conservedthroughout evolution, DNA damage response pathwayshave predictably become even more complex in eukaryotes. In terms of cancer causation, the critical role forDNA damage responses is demonstrated by the fact thata number of human cancer susceptibility syndromes arecaused by inherited mutations affecting proteins involvedin DNA damage responses. For example, inherited mutations in damage-response genes can lead to skin cancers(xeroderma pigmentosum genes), leukemias and lymphomas (ATM, Fanconi anemia genes), breast and ovarian cancers (p53, Brca1, Brca2), colon cancers (mismatchrepair genes), and brain tumors (p53). The epidemiologicobservation that exposure to environmental DNA damaging agents contributes to at least 80% of all human cancers (Doll and Peto 1981) further illustrates the importance of these responses in cancer causation. Since manyof our cancer therapeutic interventions attempt to kill tumor cells via targeting the DNA, gene products involvedin DNA damage response pathways are also predictablycritical for determining therapeutic outcomes. Thus, elucidation of the mechanisms involved in DNA damage response pathways for both understanding cancer causationand eliciting cancer cures has obvious importance. Thep53 and ATM gene products are critical in cellular responses to DNA damage, particularly DNA strand breakssuch as those induced by ionizing irradiation, and are thefocus of this discussion...