Genome instability in cancer: telomeres and DNA repair

项目摘要 这个项目的重点是端粒和DSB修复在癌症基因组不稳定中的作用。众多新近 WGS的研究表明，大多数癌症基因组都带有显著的结构变化， 确认有必要了解这种基因组不稳定性是如何产生的。在这种背景下，我们的工作提出了如何 端粒影响肿瘤的发生，强调端粒在癌症中的两个主要贡献：端粒 端粒肿瘤抑制途径与端粒驱动的基因组不稳定性。在本供资期间， 我们已经为端粒肿瘤抑制通路提供了遗传学证据，并证明了正确的 在出生时设定端粒长度可以预防多种组织中的癌症。我们已经剖析了这一机制 通过端粒危机，在检查点缺陷中端粒缩短导致基因组不稳定的阶段 癌症克隆，引发断裂-融合-桥(BFB)周期、染色质增多症和卡特吉斯。我们有 提供了端粒酶可以在DSB产生新的端粒(新端粒)的第一个证据，并提出了 新端粒的形成可以通过增加细胞的适合度来塑造癌症基因组。 正在进行的BFB循环。最后，我们的实验室继续研究53BP1在DSB修复和PARPI中的作用 对BRCA1缺陷细胞的处理表明，与通常认为的不同，53BP1不会阻断 切除，但招募CST-Pola/Primase复合体来填充切除的DNA末端。这些发现奠定了基础 对于我们未来的工作，我们的目标是继续我们的开创性研究和对未来癌症的指导 研究人员。我们将会推行的计划例子包括： 1.采用创新的方法，我们将使用CRISPRi筛子来抑制新端粒 形成和查询癌症中基因丢失/突变的命中。 2.我们提出新端粒的形成可以终止BFB周期，提高BFB的活性 具有双着丝粒染色体的细胞将在体外模型中进行测试，以诱导BFB周期。 3.为了更深入地了解端粒肿瘤抑制通路，我们将确定如何 端粒长度是受调节的。 4.最近的一项研究表明，端粒较短的癌细胞株 对端粒因子CST和TRF1的丢失敏感，我们将确定其机制基础 这些漏洞希望我们的洞察力可以指向新的治疗方法。 我们的目标是深入了解癌症基因组是如何改变的，首要目标是提供 肿瘤学家的信息可以为他们在诊断、治疗和预防方面的决策提供信息。 1

Project Summary This project focuses on the role of telomeres and DSB repair in genome instability in cancer. Numerous recent WGS studies have revealed that most cancer genomes carry a remarkable level of structural changes, affirming the need to understand how this genome instability arises. In this context, our work asks how telomeres affect tumorigenesis with emphasis on the two major contributions of telomeres in cancer: the telomere tumor suppressor pathway and telomere-driven genome instability. During the current funding period, we have provided genetic evidence for the telomere tumor suppressor pathway and showed that the correct telomere length setting at birth prevents cancer in a wide range of tissues. We have dissected the mechanism by which telomere crisis, a stage at which telomere shortening drives genome instability in checkpoint-deficient cancer clones, instigates breakage-fusion-bridge (BFB) cycles, chromothripsis, and kataegis. We have provided the first evidence that telomerase can create new telomeres (neotelomeres) at DSBs and propose that neotelomere formation can mold the cancer genome by increasing the fitness of cells struggling with ongoing BFB cycles. Finally, our lab continued its work on the role of 53BP1 in DSB repair and PARPi treatment of BRCA1-deficient cells, showing that, unlike what was generally believed, 53BP1 does not block resection but recruits the CST-Pola/primase complex to fill-in resected DNA ends. These findings set the stage for our future work, in which we aim to continue our path-breaking research and the mentoring of future cancer researchers. Examples of projects we will pursue are: 1. Using an innovative approach, we will use CRISPRi screens for repressors of neotelomere formation and query hits for gene loss/mutation in cancer. 2. Our proposal that neotelomere formation can terminate BFB cycles and enhance the viability of cells with dicentric chromosomes will be tested in an in vitro model for induction of BFB cycles. 3. To gain deeper insights into the telomere tumor suppressor pathway, we will determine how telomere length is regulated. 4. Following a recent demonstration that cancer cell lines with short telomeres are exceptionally sensitive to loss of the telomeric factors CST and TRF1, we will determine the mechanistic basis of these vulnerabilities in hopes that our insights may point to new treatments. Our aim is to derive deep insights into how cancer genomes are altered with the overarching goal of providing oncologists with information that can inform their decisions on diagnosis, treatment, and prevention. 1