scholarly journals Replication gaps are a cancer vulnerability counteracted by translesion synthesis

2019 ◽  
Author(s):  
Sumeet Nayak ◽  
Jennifer A. Calvo ◽  
Ke Cong ◽  
Emily Berthiaume ◽  
Jessica Jackson ◽  
...  
Keyword(s):  
Electron Microscopy ◽  
Dna Damage ◽  
Stress Response ◽  
Cancer Cell ◽  
Replication Fork ◽  
Translesion Synthesis ◽  
Cancer Therapies ◽  
Fiber Analysis ◽  
Molecule Inhibitor ◽  
Anti Cancer

SUMMARYThe replication stress response which serves as an anti-cancer barrier is activated not only by DNA damage and replication obstacles, but also oncogenes, mystifying how cancer evolves. Here, we identify that oncogene expression, similar to cancer therapies, induces single stranded DNA (ssDNA) gaps that reduce cell fitness, unless suppressed by translesion synthesis (TLS). DNA fiber analysis and electron microscopy reveal that TLS restricts replication fork slowing, reversal, and fork degradation without inducing replication fork gaps. Evidence that TLS gap suppression is fundamental to cancer, a small molecule inhibitor targeting the TLS factor, REV1, not only disrupts DNA replication and cancer cell fitness, but also synergizes with gap-inducing therapies. This work illuminates that gap suppression during replication is critical for cancer cell fitness and therefore a targetable vulnerability.

scholarly journals Inhibition of the translesion synthesis polymerase REV1 exploits replication gaps as a cancer vulnerability

2020 ◽  
Vol 6 (24) ◽  
pp. eaaz7808 ◽  
Author(s):  
Sumeet Nayak ◽  
Jennifer A. Calvo ◽  
Ke Cong ◽  
Min Peng ◽  
Emily Berthiaume ◽  
...  
Keyword(s):  
Electron Microscopy ◽  
Dna Damage ◽  
Stress Response ◽  
Cancer Cell ◽  
Small Molecule ◽  
Replication Fork ◽  
Translesion Synthesis ◽  
Replication Stress ◽  
Fiber Analysis ◽  
Molecule Inhibitor

The replication stress response, which serves as an anticancer barrier, is activated not only by DNA damage and replication obstacles but also oncogenes, thus obscuring how cancer evolves. Here, we identify that oncogene expression, similar to other replication stress–inducing agents, induces single-stranded DNA (ssDNA) gaps that reduce cell fitness. DNA fiber analysis and electron microscopy reveal that activation of translesion synthesis (TLS) polymerases restricts replication fork slowing, reversal, and fork degradation without inducing replication gaps despite the continuation of replication during stress. Consistent with gap suppression (GS) being fundamental to cancer, we demonstrate that a small-molecule inhibitor targeting the TLS factor REV1 not only disrupts DNA replication and cancer cell fitness but also synergizes with gap-inducing therapies such as inhibitors of ATR or Wee1. Our work illuminates that GS during replication is critical for cancer cell fitness and therefore a targetable vulnerability.

scholarly journals Maturation of telomere 3’-overhangs is linked to the replication stress response

2020 ◽  
Author(s):  
Erin E. Henninger ◽  
Pascale Jolivet ◽  
Emilie Fallet ◽  
Mohcen Benmounah ◽  
Zhou Xu ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Stress Response ◽  
Ubiquitin Ligase ◽  
Replication Fork ◽  
Damage Tolerance ◽  
Dna Helicase ◽  
Dna Damage Tolerance ◽  
Telomeric Repeats ◽  
Telomere Replication

AbstractPassage of the replication fork through telomeric repeats necessitates additional DNA processing by DNA repair factors, to regenerate the terminal 3’-overhang structure at leading telomeres. These factors are prevented from promoting telomeric recombination or fusion by an uncharacterized mechanism. Here we show that Rad5, a DNA helicase and ubiquitin ligase involved in the DNA damage tolerance pathway, participates in this mechanism. Rad5 is enriched at telomeres during telomere replication. Accelerated senescence seen in the absence of telomerase and Rad5, can be compensated for by a pathway involving the Rad51 recombinase and counteracted by the helicase Srs2. However, this pathway is only active at short telomeres. Instead, the ubiquitous activity of Rad5 during telomere replication is necessary for the proper reconstitution of the telomeric 3’-overhang, indicating that Rad5 is required to coordinate telomere maturation during telomere replication.

scholarly journals DNA Repair Pathways in Cancer Therapy and Resistance

2021 ◽  
Vol 11 ◽  
Author(s):  
Lan-ya Li ◽  
Yi-di Guan ◽  
Xi-sha Chen ◽  
Jin-ming Yang ◽  
Yan Cheng
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Mammalian Cells ◽  
Chemotherapeutic Agents ◽  
Cancer Therapies ◽  
Exogenous Dna ◽  
Dna Damaging Agents ◽  
Anti Cancer ◽  
Mitochondria Dna ◽  
Repair Pathways

DNA repair pathways are triggered to maintain genetic stability and integrity when mammalian cells are exposed to endogenous or exogenous DNA-damaging agents. The deregulation of DNA repair pathways is associated with the initiation and progression of cancer. As the primary anti-cancer therapies, ionizing radiation and chemotherapeutic agents induce cell death by directly or indirectly causing DNA damage, dysregulation of the DNA damage response may contribute to hypersensitivity or resistance of cancer cells to genotoxic agents and targeting DNA repair pathway can increase the tumor sensitivity to cancer therapies. Therefore, targeting DNA repair pathways may be a potential therapeutic approach for cancer treatment. A better understanding of the biology and the regulatory mechanisms of DNA repair pathways has the potential to facilitate the development of inhibitors of nuclear and mitochondria DNA repair pathways for enhancing anticancer effect of DNA damage-based therapy.

scholarly journals Melanoma subpopulations that rapidly escape MAPK pathway inhibition incur DNA damage and rely on stress signalling

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Chen Yang ◽  
Chengzhe Tian ◽  
Timothy E. Hoffman ◽  
Nicole K. Jacobsen ◽  
Sabrina L. Spencer
Keyword(s):  
Dna Damage ◽  
Drug Resistance ◽  
Mapk Pathway ◽  
Melanoma Cells ◽  
Cancer Therapies ◽  
Braf Inhibitors ◽  
Anti Cancer ◽  
Genetic Mechanisms ◽  
Pathway Inhibition ◽  
Stress Signalling

AbstractDespite the increasing number of effective anti-cancer therapies, successful treatment is limited by the development of drug resistance. While the contribution of genetic factors to drug resistance is undeniable, little is known about how drug-sensitive cells first evade drug action to proliferate in drug. Here we track the responses of thousands of single melanoma cells to BRAF inhibitors and show that a subset of cells escapes drug via non-genetic mechanisms within the first three days of treatment. Cells that escape drug rely on ATF4 stress signalling to cycle periodically in drug, experience DNA replication defects leading to DNA damage, and yet out-proliferate other cells over extended treatment. Together, our work reveals just how rapidly melanoma cells can adapt to drug treatment, generating a mutagenesis-prone subpopulation that expands over time.

scholarly journals Selective small molecule PARG inhibitor causes replication fork stalling and cancer cell death

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Jerry H. Houl ◽  
Zu Ye ◽  
Chris A. Brosey ◽  
Lakshitha P. F. Balapiti-Modarage ◽  
Sarita Namjoshi ◽  
...  
Keyword(s):  
Dna Damage ◽  
Cell Survival ◽  
Cancer Cell ◽  
Replication Fork ◽  
Competitive Inhibition ◽  
Parp Inhibitor ◽  
Inhibition Mechanism ◽  
Binding Modes ◽  
Chemical Library ◽  
Cancer Cell Survival

AbstractPoly(ADP-ribose)ylation (PARylation) by PAR polymerase 1 (PARP1) and PARylation removal by poly(ADP-ribose) glycohydrolase (PARG) critically regulate DNA damage responses; yet, conflicting reports obscure PARG biology and its impact on cancer cell resistance to PARP1 inhibitors. Here, we found that PARG expression is upregulated in many cancers. We employed chemical library screening to identify and optimize methylxanthine derivatives as selective bioavailable PARG inhibitors. Multiple crystal structures reveal how substituent positions on the methylxanthine core dictate binding modes and inducible-complementarity with a PARG-specific tyrosine clasp and arginine switch, supporting inhibitor specificity and a competitive inhibition mechanism. Cell-based assays show selective PARG inhibition and PARP1 hyperPARylation. Moreover, our PARG inhibitor sensitizes cells to radiation-induced DNA damage, suppresses replication fork progression and impedes cancer cell survival. In PARP inhibitor-resistant A172 glioblastoma cells, our PARG inhibitor shows comparable killing to Nedaplatin, providing further proof-of-concept that selectively inhibiting PARG can impair cancer cell survival.

scholarly journals Astaxanthin Reduces Stemness Markers in BT20 and T47D Breast Cancer Stem Cells by Inhibiting Expression of Pontin and Mutant p53

Marine Drugs ◽  
2020 ◽  
Vol 18 (11) ◽  
pp. 577
Author(s):  
Yong Tae Ahn ◽  
Min Sung Kim ◽  
Youn Sook Kim ◽  
Won Gun An
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Breast Cancer Cell ◽  
Breast Cancer Cells ◽  
Cancer Cell Line ◽  
Migration And Invasion ◽  
Breast Cancer Cell Lines ◽  
Cancer Therapies ◽  
Anti Cancer

Astaxanthin (AST) is a product made from marine organisms that has been used as an anti-cancer supplement. It reduces pontin expression and induces apoptosis in SKBR3, a breast cancer cell line. Using Western blotting and qRT-PCR analyses, this study revealed that in the T47D and BT20 breast cancer cell lines, AST inhibits expression of pontin and mutp53, as well as the Oct4 and Nanog cancer stem cell (CSC) stemness genes. In addition, we explored the mechanism by which AST eradicates breast cancer cells using pontin siRNAs. Pontin knockdown by pontin siRNA reduced proliferation, Oct4 and Nanog expression, colony and spheroid formation, and migration and invasion abilities in breast cancer cells. In addition, reductions in Oct4, Nanog, and mutp53 expression following rottlerin treatment confirmed the role of pontin in these cells. Therefore, pontin may play a central role in the regulation of CSC properties and in cell proliferation following AST treatment. Taken together, these findings demonstrate that AST can repress CSC stemness genes in breast cancer cells, which implies that AST therapy could be used to improve the efficacy of other anti-cancer therapies against breast cancer cells.

scholarly journals Diversity and Biology of Cancer-Associated Fibroblasts

2021 ◽  
Vol 101 (1) ◽  
pp. 147-176 ◽  
Author(s):  
Giulia Biffi ◽  
David A. Tuveson
Keyword(s):  
Cancer Cell ◽  
Therapy Resistance ◽  
The Body ◽  
Cancer Therapies ◽  
Cancer Associated Fibroblasts ◽  
Anti Cancer ◽  
Cancer Cell Survival ◽  
Epithelial Compartment ◽  
Cancer Types ◽  
Immune Exclusion

Efforts to develop anti-cancer therapies have largely focused on targeting the epithelial compartment, despite the presence of non-neoplastic stromal components that substantially contribute to the progression of the tumor. Indeed, cancer cell survival, growth, migration, and even dormancy are influenced by the surrounding tumor microenvironment (TME). Within the TME, cancer-associated fibroblasts (CAFs) have been shown to play several roles in the development of a tumor. They secrete growth factors, inflammatory ligands, and extracellular matrix proteins that promote cancer cell proliferation, therapy resistance, and immune exclusion. However, recent work indicates that CAFs may also restrain tumor progression in some circumstances. In this review, we summarize the body of work on CAFs, with a particular focus on the most recent discoveries about fibroblast heterogeneity, plasticity, and functions. We also highlight the commonalities of fibroblasts present across different cancer types, and in normal and inflammatory states. Finally, we present the latest advances regarding therapeutic strategies targeting CAFs that are undergoing preclinical and clinical evaluation.

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