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，是人类基因组不稳定的一个主要来源 癌细胞，也是癌症的脆弱性，可以在治疗上进行靶向治疗。PARP最近的成功 治疗BRCA突变肿瘤的抑制剂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压力的理解仍然是 非常有限。尽管我们知道癌细胞中的许多不同致癌事件可以导致复制 问题，我们仍然不完全了解这些致癌事件是否影响类似或类似的 不同的方式。此外，我们对不同致癌基因如何改变DNA复制也知之甚少。 事件，以及改变的复制是否会引起明显的细胞脆弱性。了解基本知识 复制应激的分子特征，癌细胞复制应激的主要原因，以及不同 复制更改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。 长期以来，我一直对了解人类细胞中的复制应激反应感兴趣。尤其是，我的 实验室已经广泛研究了ATR检查点通路的功能和调节，ATR检查点通路是ATR检查点通路的主要调节因子 人类细胞中的复制应激反应。我们的工作对目前的压力模型做出了重大贡献 DNA复制过程中的感知和信号传递。从我们和其他人最近的研究来看，它已经逐渐成为 清楚的是，癌细胞中不同的致癌事件会在DNA复制中产生不同的问题。 此外，转录产物rna转录本对dna既有积极的影响，也有消极的影响。 复制和修复。我们的研究还表明，复制应激不仅对细胞产生自主效应 对基因组的影响，也是细胞群体中细胞的非自治效应。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，并探索复制对细胞的非自主影响 肿瘤微环境中的应激与癌症治疗。这些研究可能会为我们提供更多 全面了解癌细胞复制应激的分子基础及其影响 肿瘤微环境中癌细胞的基因组和细胞群，以及癌细胞的特异性 它们所引起的脆弱性。来自这些研究的新概念和发现可能会产生革命性的影响 对癌症研究和癌症治疗的影响。

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.