Parp Function in Prostate Cancer

摘要 雄激素受体(AR)对前列腺生物学有深远的贡献 癌细胞，主要通过其作为配体调节的转录因子的功能。AS 前列腺癌的这种治疗方法通常被设计为消耗或 与内源性雄激素竞争，目的是降低转录功能 应变率。这项提议涉及一个相对未被探索的AR行动领域，这就是它如何 产生DNA损伤并对其做出反应。简而言之，我们开发了一套大型的 初步数据显示，AR是由雄激素启动的信号轴的一部分， 需要来自DNA损伤和修复机制的输入，并导致组装 一个DNA修复复合体。我们发现这个途径中的一个关键酶是Parp7， 一种单-ADP-核糖基转移酶，对其知之甚少。在Aim1中，我们将确定如何 Parp7受前列腺癌细胞中雄激素和DNA损伤信号的调节。在……里面 AIM2我们将确定Parp7如何调节细胞的组装和DNA修复功能 E3泛素连接酶/ADP-核糖基转移酶复合体。在Aim3中，我们将定义 信号轴在基因组维持、肿瘤发生和治疗中的作用 回应。介导DNA损伤反应和修复反应的酶有 成为包括前列腺癌在内的恶性肿瘤的可操作靶点。阻滞剂 多聚ADP-核糖基转移酶家族成员PARP1可以改善治疗结果- 耐药前列腺癌，尽管其益处取决于DNA修复的状态 机械，特别是BRCA1/BRCA2基因。因此，虽然临床发现 为靶向DNA修复途径提供原则证据，它们还强调 定义和纳入生化和基因组环境的重要性 治疗的基本原理。总而言之，我们的研究将定义生化关系 在雄激素信号和DNA损伤和修复途径之间，并帮助提供 对前列腺癌细胞脆弱性的新见解。

ABSTRACT The androgen receptor (AR) makes profound contributions to the biology of prostate cancer cells, principally through its function as a ligand-regulated transcription factor. As such, therapeutic approaches to prostate cancer are typically designed to deplete or compete with endogenous androgens with the goal of reducing the transcription function of AR. This proposal addresses a relatively unexplored area of AR action, which is how it generates and responds to DNA damage. In brief, we have developed a large set of preliminary data that shows AR is part of an signaling axis that is initiated by androgen, requires inputs from the DNA damage and repair machinery, and results in assembly of a DNA repair complex. We found that one of the key enzymes in this pathway is Parp7, a mono-ADP-ribosytransferase for which little is known. In Aim1 we will determine how Parp7 is regulated by androgen and DNA damage signaling in prostate cancer cells. In Aim2 we will determine how Parp7 regulates the assembly and DNA repair function of an E3 ubiquitin ligase/ADP-ribosyltransferase complex. In Aim3 we will define the contribution of the signaling axis to genome maintenance, tumorigenesis, and therapy response. The enzymes that mediate DNA damage response and repair reactions have emerged as actionable targets in malignancies including prostate cancer. Inhibitors to the poly-ADP-ribosyltransferase family member, Parp1, improve outcomes in therapy- resistant prostate cancer, though the benefit depends on the status of the DNA repair machinery, notably the BRCA1/BRCA2 genotype. Thus, while the clinical findings provide proof-of-principle for targeting DNA repair pathways, they also underscore the importance of defining and incorporating biochemical and genomic context into treatment rationale. In summary, our studies will define the biochemical relationships between androgen signaling and DNA damage and repair pathways, and help provide new insights into the vulnerabilities of prostate cancer cells.