Genome instability in cancer: telomeres and DNA repair

癌症中的基因组不稳定性：端粒和 DNA 修复

基本信息

批准号：
10736646
负责人：
Titia de Lange
金额：
$ 100.78万
依托单位：
ROCKEFELLER UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-02 至 2030-08-31
项目状态：
未结题

项目摘要

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

项目摘要该项目着重于端粒和DSB修复在基因组不稳定性中的作用。最近的许多 WGS研究表明，大多数癌症基因组具有显着水平的结构变化，确认需要了解该基因组不稳定性的需求。在这种情况下，我们的工作询问如何端粒会影响肿瘤发生，重点是癌症中端粒的两个主要贡献：端粒肿瘤抑制途径和端粒驱动的基因组不稳定性。在当前的资金期间，我们为端粒肿瘤抑制途径提供了遗传证据，并表明正确端粒的长度设置可防止癌症在广泛的组织中。我们已经解剖了机制通过哪个端粒危机，端粒缩短驱动基因组不稳定的阶段癌症克隆，刺激融合桥（BFB）周期，铬骨和kataegis。我们有提供了第一个证据，表明端粒酶可以在DSB上创建新的端粒（Neotelomeres）并提出 Neotelomere的形成可以通过增加苦苦挣扎的细胞的适应性来塑造癌症基因组正在进行的BFB周期。最后，我们的实验室继续其在53BP1在DSB维修和PARPI中的作用治疗BRCA1缺陷型细胞，表明与通常认为的细胞不同，53BP1不阻止切除，但将CST-POLA/PRIMASE配合物募集到切除的DNA末端。这些发现设定了舞台为了我们未来的工作，我们旨在继续我们的突破性研究和对未来癌症的指导研究人员。我们将追求的项目的示例是： 1。使用创新的方法，我们将使用CRISPRI屏幕进行新Otelomere的阻遏物癌症中基因丧失/突变的形成和查询。 2。我们提出的，关于新旋转组的形成可以终止BFB周期并增强的生存能力将在体外模型中测试含二含染色体的细胞，以诱导BFB循环。 3。为了更深入地了解端粒肿瘤抑制途径，我们将确定如何端粒长度受到调节。 4。最近一次证明，端粒较短的癌细胞系异常对端粒因子CST和TRF1的丢失敏感，我们将确定这些脆弱性希望我们的见解可以指向新的治疗方法。我们的目标是深入了解如何通过提供的总体目标来改变癌症基因组肿瘤学家提供的信息可以告知他们关于诊断，治疗和预防的决定。 1

项目成果

期刊论文数量（11）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

CST-Polα/Primase: the second telomere maintenance machine.

DOI：
10.1101/gad.350479.123
发表时间：
2023-07-01
期刊：
GENES & DEVELOPMENT
影响因子：
10.5
作者：
Cai, Sarah W.;de Lange, Titia
通讯作者：
de Lange, Titia

CST/Polα/primase-mediated fill-in synthesis at DSBs.

DOI：
10.1080/15384101.2022.2123886
发表时间：
2023-03
期刊：
Cell cycle (Georgetown, Tex.)
影响因子：
0
作者：
Mirman Z;Cai S;de Lange T
通讯作者：
de Lange T

TINF2 is a haploinsufficient tumor suppressor that limits telomere length.

DOI：
10.7554/elife.61235
发表时间：
2020-12-01
期刊：
eLife
影响因子：
7.7
作者：
Schmutz I;Mensenkamp AR;Takai KK;Haadsma M;Spruijt L;de Voer RM;Choo SS;Lorbeer FK;van Grinsven EJ;Hockemeyer D;Jongmans MC;de Lange T
通讯作者：
de Lange T

Nuclear Envelope Rupture Is Enhanced by Loss of p53 or Rb.

DOI：
10.1158/1541-7786.mcr-17-0084
发表时间：
2017-11
期刊：
Molecular cancer research : MCR
影响因子：
0
作者：
Yang Z;Maciejowski J;de Lange T
通讯作者：
de Lange T

Most large structural variants in cancer genomes can be detected without long reads.

DOI：
10.1038/s41588-023-01540-6
发表时间：
2023-12
期刊：
NATURE GENETICS
影响因子：
30.8
作者：
Choo, Zi-Ning;Behr, Julie M.;Deshpande, Aditya;Hadi, Kevin;Yao, Xiaotong;Tian, Huasong;Takai, Kaori;Zakusilo, George;Rosiene, Joel;Paula, Arnaud Da Cruz;Weigelt, Britta;Setton, Jeremy;Riaz, Nadeem;Powell, Simon N.;Busam, Klaus;Shoushtari, Alexander N.;Ariyan, Charlotte;Reis-Filho, Jorge;de Lange, Titia;Imielinski, Marcin
通讯作者：
Imielinski, Marcin