ROLE OF ATAXIA TELANGIECTASIA IN CHECKPOINT CONTROL

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Radiation is an important and effective component of cancer therapy but its success relies largely on the radio-sensitivity of tumor cells. As the genetic composition of a tumor cell is one of the major determinants of radio-resistance, understanding the biochemical and molecular pathways in normal and tumor cells that determines whether they should the DNA damage and progress through the cell cycle or that they should undergo apoptosis is paramount in developing more effective ways to deal with radio- resistant tumors. The long-term goal of our research is to determine the molecular pathways that specify radiation-induced DNA damage checkpoint control. The ability to identify and manipulate key components of this system should allow for development of more effective radiotherapeutic strategies and provide reliable markers for predicting tumor response to radio-therapy. The goals of this proposal are to characterize the molecular and biochemical functions of the ATM protein (ataxia telangiectasia mutated) and its associated proteins as step towards understanding the molecular mechanism of a checkpoint control in human cells. Using highly specific ATM antibodies, we show that radiation induces a kinase activity that is tightly associated with ATM. We will examine the biochemical mechanism by which radiation activates ATM kinase as well as characterize proteins that act in conjunction with ATM to activate checkpoint control. We have identified four candidate proteins that associate with ATM and we propose to examine the molecular basis of these interactions as a function of DNA damage and cell cycle control. The detained analysis of the biochemical and molecular proteins of ATM should contribute in a significant way towards defining the molecular response to radiation induced DNA damage.