Abstract PL04-02: ATM: Bridging DNA damage responses and metabolic regulation

Abstract

Abstract Much of our understanding of the mechanisms involved in cellular DNA damage response pathways have come from studies of human cancer susceptibility syndromes. ATM, the gene mutated in the cancer-prone, radiosensitive disorder, Ataxia-telangiectasia (A-T), is a protein kinase that is a central mediator of responses to DNA double strand breaks in cells. Once activated, ATM phosphorylates numerous substrates in the cell that modulate the cell's response to the DNA damage. p53, one of the many targets of the ATM kinase, is a critical mediator of cell cycle changes and cell death signaling following DNA damage and other stresses. Though ATM clearly plays a central role in mediating cellular responses to DNA breakage, some of the clinical abnormalities in A-T are difficult to attribute directly to alterations in DNA damage signaling. The broad-based symptoms in A-T and recently acquired data suggest that ATM has physiologic roles that extend beyond its regulation of DNA damage responses. In particular, ATM appears to affect insulin signaling pathways and to have a direct role in regulating mitochondrial function. Interestingly, we found in mouse models of A-T that these mitochondrial defects associated with ATM deficiency appear to be a contributing factor to cancer development in A-T. These new insights suggest that Ataxia-Telangiectasia should be considered, at least in part, as a mitochondrial dysfunction disease and provide links between cancer-related DNA damage signaling, general metabolic signaling pathways, and cancer development. Citation Format: Michael B. Kastan, Yasmine Valentin-Vega, Adam Brown, Peter Scarbrough, Donald Fleenor. ATM: Bridging DNA damage responses and metabolic regulation. [abstract]. In: Proceedings of the Thirteenth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2014 Sep 27-Oct 1; New Orleans, LA. Philadelphia (PA): AACR; Can Prev Res 2015;8(10 Suppl): Abstract nr PL04-02.