Rewiring of epigenetic DNA damage response pathways in HPV-induced cancer

项目摘要/摘要 感染人乳头瘤病毒(HPV)导致颈部、头颈部和肛门的地方性疾病 癌症。放射治疗是这些肿瘤治疗的基石。然而，慢性阻塞性肺疾病患者的临床结果 由于复发率高，局部晚期疾病仍然很差。因此，迫切需要改进 放射治疗这些肿瘤的疗效。表观遗传信号通路在DNA损伤反应中起关键作用 为提高放射治疗疗效提供合适的临床靶点。我们证明了 HPV蛋白E6和E7改变癌细胞的表观遗传信号。我们假设这些表观基因组 改变导致肿瘤依赖于替代的表观遗传途径来应对DNA损伤。使用 CRISPR/Cas9筛选我们发现HPV阳性癌细胞选择性地依赖于染色质修饰物 NSL1和E3泛素连接酶RNF168在辐射中存活。这项提案的目标是确定 人乳头瘤病毒感染过程中DNA损伤反应(DDR)的调控机制 表观遗传变化。我们的工作将建立一个新的肿瘤靶向治疗的概念，通过利用HPV- 诱导表观基因组改变，以允许特定靶向癌细胞，同时保留健康组织。这项工作 在这里提出的将在丹尼斯·哈拉汉博士的指导下进行，他是临床和实验的领导者 放射肿瘤学。应聘者是医学博士/博士，接受过临床放射肿瘤学方面的培训，寻求进一步 基础研究方面的培训。他的长期目标是建立一个独立的研究实验室，研究 表观遗传学在DDR中的作用。预计该项目将对下列领域作出有影响力的贡献 DDR和放射肿瘤学，并为候选人作为一名独立调查员的职业生涯做好准备。

Project summary/abstract Infection with human papilloma virus (HPV) causes endemic occurrence of cervical, head and neck and anal cancers. Radiotherapy is the cornerstone treatment for these tumors. However, clinical outcomes in patients with locally advanced disease remain poor due to high recurrence rates. Thus, there is a critical need to improve the efficacy of radiation in these tumors. Epigenetic signaling pathways play a crucial role in DNA damage response providing suitable clinical targets for improving the efficacy of radiotherapy. We demonstrate that expression of the HPV proteins E6 and E7 alters epigenetic signaling in cancer cells. We hypothesize that these epigenomic alterations cause tumor dependence on alternative epigenetic pathways to cope with DNA damage. Using a CRISPR/Cas9 screen we discovered that HPV-positive cancer cells selectively depend on the chromatin modifier NSL1 and the E3 ubiquitin ligase RNF168 to survive radiation. The goal of this proposal is to determine the mechanisms of DNA damage response (DDR) regulated by these pathways in the setting of HPV-induced epigenetic changes. Our work will establish a novel concept of tumor-targeted therapy by harnessing HPV- induced epigenomic alterations to allow specific targeting of cancer cells while sparing healthy tissues. The work proposed here will be conducted under the mentorship of Dr. Dennis Hallahan, a leader clinical and experimental radiation oncology. The candidate is an MD/PhD with training in clinical radiation oncology who seeks further training in basic research. His long-term goal is to establish an independent research laboratory studying the role of epigenetics in DDR. It is anticipated that the project will result in impactful contributions to the fields of DDR and Radiation Oncology and prepare the candidate for a career as an independent investigator.