NPDA page 1 Titia de Lange A new approach to the DNA damage response Significance The biological response to DNA damage is a central issue in modern biology that has attracted the attention of outstanding investigators. The continuity of life depends on the ability of cells to protect their DNA from intrinsic and extrinsic damage and deficiencies in the DNA damage response can contribute to tumorigenesis, aspects of aging, hereditary disorders, and fertility problems. All eukaryotic cells respond to DNA breaks (DSBs) and other lesions through a signaling pathway that governs cell cycle progression and controls aspects of DNA repair. The information flow is carried by a set of protein kinases, such as ATM, ATR, Chk1, and Chk2, that emerged from genetic screens in yeast and studies of human chromosome breakage syndromes. Although the mechanism of signal transduction and at least some of the targets of these kinases are known, we do not know how DNA damage is detected and the players in this sensing step have remained largely unknown. In order for the field to fulfill its promise for the improvement of human health, the study of DNA damage sensing needs to take a new direction. Here I describe my plans to force an inflection point in our acquisition of knowledge in this area. The experiments are designed to address the major outstanding questions in the field: what is the signal that activates the pathway (e.g. a DNA end, an altered DNA structure, or an altered nucleosomal configuration), how is the signal sensed (which new or known proteins are the first to arrive at the lesion), and how do the sensors interface with the known transducers of the pathway? Limitations of the current approaches The technology currently available to study the mammalian DNA damage response has three major drawbacks: the absence of a molecular mark at the
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