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 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 MELK-T1, a small-molecule inhibitor of protein kinase MELK, decreases DNA-damage tolerance in proliferating cancer cells

2015 ◽  
Vol 35 (6) ◽  
Author(s):  
Lijs Beke ◽  
Cenk Kig ◽  
Joannes T. M. Linders ◽  
Shannah Boens ◽  
An Boeckx ◽  
...  
Keyword(s):  
Dna Damage ◽  
Protein Kinase ◽  
Cancer Cells ◽  
Small Molecule ◽  
Damage Tolerance ◽  
Replication Stress ◽  
Small Molecule Inhibitor ◽  
Dna Damage Tolerance ◽  
Molecule Inhibitor ◽  
Senescence Phenotype

Protein kinase MELK has oncogenic properties and is highly overexpressed in some tumors. In the present study, we show that a novel MELK inhibitor causes both the inhibition and degradation of MELK, culminating in replication stress and a senescence phenotype.

scholarly journals High Risk α-HPV E6 Impairs Translesion Synthesis by Blocking POLη Induction

Cancers ◽  
2020 ◽  
Vol 13 (1) ◽  
pp. 28
Author(s):  
Sebastian O. Wendel ◽  
Jazmine A. Snow ◽  
Tyler Bastian ◽  
Laura Brown ◽  
Candy Hernandez ◽  
...  
Keyword(s):  
Dna Damage ◽  
High Risk ◽  
Replication Fork ◽  
Ex Vivo ◽  
Translesion Synthesis ◽  
Replication Stress ◽  
Human Papillomaviruses ◽  
Hpv16 E6 ◽  
Hpv E6

High risk genus α human papillomaviruses (α-HPVs) express two versatile oncogenes (α-HPV E6 and E7) that cause cervical cancer (CaCx) by degrading tumor suppressor proteins (p53 and RB). α-HPV E7 also promotes replication stress and alters DNA damage responses (DDR). The translesion synthesis pathway (TLS) mitigates DNA damage by preventing replication stress from causing replication fork collapse. Computational analysis of gene expression in CaCx transcriptomic datasets identified a frequent increased expression of TLS genes. However, the essential TLS polymerases did not follow this pattern. These data were confirmed with in vitro and ex vivo systems. Further interrogation of TLS, using POLη as a representative TLS polymerase, demonstrated that α-HPV16 E6 blocks TLS polymerase induction by degrading p53. This doomed the pathway, leading to increased replication fork collapse and sensitivity to treatments that cause replication stress (e.g., UV and Cisplatin). This sensitivity could be overcome by the addition of exogenous POLη.

OTX008, a selective small-molecule inhibitor of galectin-1, downregulates cancer cell proliferation, invasion and tumour angiogenesis

2014 ◽  
Vol 50 (14) ◽  
pp. 2463-2477 ◽  
Author(s):  
Lucile Astorgues-Xerri ◽  
Maria E. Riveiro ◽  
Annemilaï Tijeras-Raballand ◽  
Maria Serova ◽  
Gabriel A. Rabinovich ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Cancer Cell ◽  
Small Molecule ◽  
Small Molecule Inhibitor ◽  
Cancer Cell Proliferation ◽  
Tumour Angiogenesis ◽  
Molecule Inhibitor

scholarly journals Small molecule inhibitor of OGG1 blocks oxidative DNA damage repair at telomeres and potentiates Methotrexate anticancer effects

2020 ◽  
Author(s):  
Juan Miguel Baquero ◽  
Carlos Benítez-Buelga ◽  
Varshni Rajagopal ◽  
Zhao Zhenjun ◽  
Raúl Torres-Ruiz ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Dna Damage ◽  
Cell Lines ◽  
Small Molecule ◽  
Oxidative Dna Damage ◽  
Genome Instability ◽  
Excision Repair ◽  
Small Molecule Inhibitor ◽  
Osteosarcoma Cell ◽  
Molecule Inhibitor

Abstract Background: The most common oxidative DNA lesion is 8-oxoguanine (8-oxoG) which is mainly recognized and excised by the glycosylase OGG1, initiating the Base Excision Repair (BER) pathway. Telomeres are particularly sensitive to oxidative stress which disrupts telomere homeostasis triggering genome instability. Methods: We used U2OS OGG1-GFP osteosarcoma cell line to study the role of OGG1 at the telomeres in response to oxidative stress. Next, we investigated the effects of inactivating pharmacologically the BER during oxidative stress (OS) conditions by using a specific small molecule inhibitor of OGG1 (TH5487) in different human cell lines. Results: We have found that during OS, TH5487 effectively blocks BER initiation at telomeres causing accumulation of oxidized bases at this region, correlating with other phenotypes such as telomere losses, micronuclei formation and mild proliferation defects. Besides, the antimetabolite Methotrexate synergizes with TH5487 through induction of intracellular ROS formation, which potentiates TH5487 mediated telomere and genome instability in different cell lines. Conclusions: Our findings demonstrate that OGG1 is required to protect telomeres from OS and present OGG1 inhibitors as a tool to induce oxidative DNA damage at telomeres, with the potential for developing new combination therapies for cancer treatment.

scholarly journals KIF15 nanomechanics and kinesin inhibitors, with implications for cancer chemotherapeutics

2018 ◽  
Vol 115 (20) ◽  
pp. E4613-E4622 ◽  
Author(s):  
Bojan Milic ◽  
Anirban Chakraborty ◽  
Kyuho Han ◽  
Michael C. Bassik ◽  
Steven M. Block
Keyword(s):  
Cancer Cell ◽  
Small Molecule ◽  
Single Molecule ◽  
Small Molecule Inhibitors ◽  
Cancer Cell Growth ◽  
Combination Drug ◽  
Cancer Chemotherapeutics ◽  
Development Of Resistance ◽  
Molecule Inhibitor ◽  
Mechanochemical Cycle

Eg5, a mitotic kinesin, has been a target for anticancer drug development. Clinical trials of small-molecule inhibitors of Eg5 have been stymied by the development of resistance, attributable to mitotic rescue by a different endogenous kinesin, KIF15. Compared with Eg5, relatively little is known about the properties of the KIF15 motor. Here, we employed single-molecule optical-trapping techniques to define the KIF15 mechanochemical cycle. We also studied the inhibitory effects of KIF15-IN-1, an uncharacterized, commercially available, small-molecule inhibitor, on KIF15 motility. To explore the complementary behaviors of KIF15 and Eg5, we also scored the effects of small-molecule inhibitors on admixtures of both motors, using both a microtubule (MT)-gliding assay and an assay for cancer cell viability. We found that (i) KIF15 motility differs significantly from Eg5; (ii) KIF15-IN-1 is a potent inhibitor of KIF15 motility; (iii) MT gliding powered by KIF15 and Eg5 only ceases when both motors are inhibited; and (iv) pairing KIF15-IN-1 with Eg5 inhibitors synergistically reduces cancer cell growth. Taken together, our results lend support to the notion that a combination drug therapy employing both inhibitors may be a viable strategy for overcoming chemotherapeutic resistance.

70 A Selective Small Molecule Inhibitor of Mcl-1 Induces Bak Dependent Apoptosis in Cancer Cell Lines

2012 ◽  
Vol 48 ◽  
pp. 23
Author(s):  
D.C. Phillips ◽  
Y. Xiao ◽  
M. Bruncko ◽  
C. Park ◽  
H. Zhang ◽  
...  
Keyword(s):  
Cell Lines ◽  
Cancer Cell ◽  
Small Molecule ◽  
Cancer Cell Lines ◽  
Small Molecule Inhibitor ◽  
Molecule Inhibitor
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