Genome instability in cancer: telomeres and DNA repair

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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