Role of XPD in DNA Damage Response Pathway Choice

项目总结。XPD在DNA损伤反应途径选择中的作用 DNA损伤反应的进化是为了保护人类基因组的完整性，使其免受潜在的 内源性和外源性基因毒素的破坏性影响。成功的DNA损伤响应是由于 网络内路径之间的串扰得到了很好的协调。例如，一种复杂的平衡在 DNA修复和凋亡将基因组不稳定的可能性降至最低，基因组不稳定可能导致突变和 最终导致疾病。尽管控制DNA修复和修复的调节机制和信号通路 细胞凋亡的特征很好，是在DNA和DNA之间做出最终选择的驱动力 基因毒性应激对修复和细胞凋亡的影响尚不清楚。总体目标是理解 在核苷酸切除修复的交叉处触发适当反应的机制 (NER)和细胞凋亡途径。 NER通路在识别和修复广泛的螺旋结构中占有重要地位。 扭曲的病变，包括形成三链结构和化疗药物产生的病变。 我们团队最近的研究发现，NER蛋白XPD在触发P53- 通过H_2AX酪氨酸酶142的磷酸化反应螺旋扭曲DNA损伤的独立细胞凋亡 残留物。在目标1中，我们将确定XPD酪氨酸磷酸化如何作为一种信号机制发挥作用 介导DNA修复--细胞凋亡途径选择。在目标2中，我们将确定XPD在细胞命运中的作用 Decision与其对修复、转录和凋亡至关重要的分子特性有关。建议数 这项工作意义重大，因为DNA损伤反应网络中的通路之间的不平衡可能 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.