PROJECT SUMMARY. Role of XPD in DNA Damage Response Pathway Choice The DNA damage response has evolved to protect the integrity of the human genome against the potentially devastating effects of endogenous and exogenous genotoxins. A successful DNA damage response occurs due to well-orchestrated crosstalk between pathways within the network. For instance, an intricate balance between DNA repair and apoptosis minimizes the likelihood of genomic instability, which can lead to mutagenesis and ultimately to disease. Although the regulatory mechanism and signaling pathways controlling DNA repair and apoptosis are well characterized, the driving forces responsible for making the ultimate choice between DNA repair and apoptosis in response to genotoxic stress remain unclear. The overall goal is to understand the mechanisms involved in triggering the appropriate reaction at the intersection of the nucleotide excision repair (NER) and apoptotic pathways. The NER pathway occupies an important position in the recognition and repair of a wide array of helix- distorting lesions, including formation of triplex structures and lesions generated by chemotherapeutic agents. Recent work from our group has discovered that the NER protein, XPD occupies a central role in triggering p53- independent apoptosis in response to helix-distorting DNA damage via phosphorylation of the H2AX tyrosine142 residue. In Aim 1, we will determine how XPD tyrosine phosphorylation functions as a signaling mechanism to mediate DNA repair-apoptosis pathway choice. In Aim 2, we will determine whether XPD’s role in cell fate decisions is linked to its molecular properties essential for repair, transcription, and apoptosis. The proposed work is highly significant because imbalance between pathways within the DNA damage response network can eventually contribute to the etiology of human diseases.