Role of XPD in DNA Damage Response Pathway Choice

项目摘要。XPD在DNA损伤反应途径选择中的作用 DNA损伤反应已经发展到保护人类基因组的完整性，以防止潜在的 内源性和外源性基因毒素的破坏性影响。一个成功的DNA损伤反应发生， 到网络内路径之间精心编排的串扰。例如，一个复杂的平衡， DNA修复和细胞凋亡使基因组不稳定性的可能性最小化，基因组不稳定性可导致诱变和 最终导致疾病。虽然调控机制和信号通路控制DNA修复和 细胞凋亡已得到很好的表征，细胞凋亡是在DNA之间做出最终选择的驱动力 对遗传毒性应激的应答中的修复和凋亡仍不清楚。总体目标是了解 参与在核苷酸切除修复的交叉点触发适当反应的机制 (NER)和凋亡途径。 NER通路在识别和修复多种螺旋结构中占据重要地位， 扭曲损伤，包括三重结构的形成和化疗剂产生的损伤。 我们小组最近的工作发现，NER蛋白XPD在触发p53蛋白中起着核心作用。 通过H2 AX酪氨酸磷酸化对螺旋扭曲DNA损伤的独立凋亡142 残余物在目标1中，我们将确定XPD酪氨酸磷酸化如何作为信号机制发挥作用， 介导DNA修复-凋亡途径选择。在目标2中，我们将确定XPD在细胞命运中的作用是否 决定与其修复，转录和凋亡所必需的分子特性有关。拟议 这项工作非常重要，因为DNA损伤反应网络中通路之间的不平衡可以 最终对人类疾病的病因学做出贡献。

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.