Understanding and targeting the DNA replication stress in cancer cells

项目摘要 DNA复制问题统称为复制应激是基因组不稳定性的主要来源， 癌细胞以及癌症的脆弱性，可以作为治疗靶点。PARP最近的成功 抑制剂治疗BRCA突变型肿瘤提供了一个令人兴奋的靶向癌细胞的例子， 利用复制压力然而，我们目前对癌细胞复制应激的理解仍然是 非常有限。虽然我们知道癌细胞中许多不同的致癌事件都能引起复制 问题，我们仍然不完全了解这些致癌事件是否会影响DNA复制类似或 不同的方式。此外，我们对不同的致癌基因如何改变DNA复制也知之甚少。 事件，以及改变复制是否会引起不同的细胞脆弱性。了解基本 复制应激的分子特征，癌细胞复制应激的主要原因， 由于复制被改变而导致的漏洞将极大地增强我们检测和利用复制的能力 癌症治疗中的压力 我对人类细胞中的复制应激反应有着长期的兴趣。特别是我 实验室已经广泛研究了ATR检查点途径的功能和调节，ATR检查点途径是细胞凋亡的主要调节因子。 复制应激反应。我们的工作对当前的压力模型做出了重大贡献 DNA复制过程中的传感和信号传导。从我们和其他人最近的研究来看， 很明显，癌细胞中不同的致癌事件可以在DNA复制中产生不同的问题。 此外，RNA转录物作为转录产物，对DNA既有正面影响，也有负面影响 复制和修复。我们的研究还表明，复制应激不仅产生细胞自主效应， 对基因组的影响，以及细胞群体中的细胞非自主效应。基于这些新发现，我们 建议系统地定义和表征癌细胞中不同类型的复制应激，了解 RNA如何影响基因组中的复制和修复，并探索复制的细胞非自主效应 肿瘤微环境中的应激和癌症治疗。这些研究可能为我们提供更多 全面了解癌细胞中复制应激的分子基础， 在肿瘤微环境中的癌细胞和细胞群体的基因组上， 它们所带来的脆弱性。这些研究的新概念和发现可能具有变革性 对癌症和癌症治疗研究的影响。

Project Summary DNA replication problems collectively known as replication stress are a major sources of genomic instability in cancer cells and also a vulnerability of cancer that can be targeted therapeutically. The recent success of PARP inhibitors in the treatment of BRCA mutant tumors provided an exciting example of targeting cancer cells by exploiting replication stress. However, our current understanding of the replication stress in cancer cells is still very limited. Although we know that many different oncogenic events in cancer cells can cause replication problems, we still don't fully understand whether these oncogenic events affect DNA replication in similar or distinct ways. Furthermore, we also know little about how DNA replication is altered by different oncogenic events, and whether altered replication can give rise to distinct cellular vulnerabilities. Understanding the basic molecular features of replication stress, the major causes of replication stress in cancer cells, and the different vulnerabilities resulting from altered replication will greatly enhance our ability to detect and exploit replication stress in cancer therapy. I have a longstanding interest in understanding the replication stress response in human cells. In particular, my lab has extensively studied the functions and regulation of the ATR checkpoint pathway, the master regulator of replication stress response in human cells. Our work has contributed significantly to the current models of stress sensing and signaling during DNA replication. From recent studies by us and others, it has become gradually clear that different oncogenic events in cancer cells can generate distinct problems in DNA replication. Furthermore, RNA transcripts, the products of transcription, have both positive and negative impacts on DNA replication and repair. Our studies also revealed that replication stress not only exerts cell autonomous effects on the genome, but also cell non-autonomous effects in cell populations. Based on these new findings, we propose to systematically define and characterize different types of replication stress in cancer cells, understand how RNA affects replication and repair in the genome, and explore the cell non-autonomous effects of replication stress in tumor microenvironments and cancer therapy. These studies may provide us a much more comprehensive understanding of the molecular underpinnings of replication stress in cancer cells, their impacts on the genome of cancer cells and cell populations in tumor microenvironments, and the cancer cell-specific vulnerabilities that they give rise to. The new concepts and findings from these studies could have transformative impacts on the research of cancer and cancer therapy.