scholarly journals Shutting down the power supply for DNA repair in cancer cells

2017 ◽  
Vol 216 (2) ◽  
pp. 295-297 ◽  
Author(s):  
Marcel A.T.M. van Vugt
Keyword(s):  
Dna Repair ◽  
Homologous Recombination ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Power Supply ◽  
Metabolic Enzymes ◽  
Phosphoglycerate Mutase ◽  
Dna Damaging Agents ◽  
Cell Biol

Phosphoglycerate mutase 1 (PGAM1) functions in glycolysis. In this issue, Qu et al. (2017. J. Cell Biol. https://doi.org/10.1083/jcb.201607008) show that PGAM1 inactivation leads to nucleotide depletion, which causes defective homologous recombination–mediated DNA repair, suggesting that targeting metabolic enzymes increases cancer cell susceptibility to DNA damaging agents.

scholarly journals Survivin contributes to DNA repair by homologous recombination in breast cancer cells

2015 ◽  
Vol 155 (1) ◽  
pp. 53-63 ◽  
Author(s):  
Eloïse Véquaud ◽  
Grégoire Desplanques ◽  
Pascal Jézéquel ◽  
Philippe Juin ◽  
Sophie Barillé-Nion
Keyword(s):  
Breast Cancer ◽  
Dna Repair ◽  
Homologous Recombination ◽  
Cancer Cells ◽  
Breast Cancer Cells

scholarly journals WIP1 Promotes Homologous Recombination and Modulates Sensitivity to PARP Inhibitors

Cells ◽  
2019 ◽  
Vol 8 (10) ◽  
pp. 1258 ◽  
Author(s):  
Kamila Burdova ◽  
Radka Storchova ◽  
Matous Palek ◽  
Libor Macurek
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Homologous Recombination ◽  
Cancer Cells ◽  
Genotoxic Stress ◽  
Parp Inhibitors ◽  
Cell Cycle Checkpoint ◽  
Dna Lesion ◽  
Cycle Checkpoint ◽  
G2 Cells

Genotoxic stress triggers a combined action of DNA repair and cell cycle checkpoint pathways. Protein phosphatase 2C delta (referred to as WIP1) is involved in timely inactivation of DNA damage response by suppressing function of p53 and other targets at chromatin. Here we show that WIP1 promotes DNA repair through homologous recombination. Loss or inhibition of WIP1 delayed disappearance of the ionizing radiation-induced 53BP1 foci in S/G2 cells and promoted cell death. We identify breast cancer associated protein 1 (BRCA1) as interactor and substrate of WIP1 and demonstrate that WIP1 activity is needed for correct dynamics of BRCA1 recruitment to chromatin flanking the DNA lesion. In addition, WIP1 dephosphorylates 53BP1 at Threonine 543 that was previously implicated in mediating interaction with RIF1. Finally, we report that inhibition of WIP1 allowed accumulation of DNA damage in S/G2 cells and increased sensitivity of cancer cells to a poly-(ADP-ribose) polymerase inhibitor olaparib. We propose that inhibition of WIP1 may increase sensitivity of BRCA1-proficient cancer cells to olaparib.

scholarly journals PARP Inhibitors as a Therapeutic Agent for Homologous Recombination Deficiency in Breast Cancers

2019 ◽  
Vol 8 (4) ◽  
pp. 435 ◽  
Author(s):  
Man Keung ◽  
Yanyuan Wu ◽  
Jaydutt Vadgama
Keyword(s):  
Dna Repair ◽  
Homologous Recombination ◽  
Cancer Cells ◽  
Anticancer Agents ◽  
Excision Repair ◽  
Parp Inhibitor ◽  
Predictive Biomarkers ◽  
Parp Inhibitors ◽  
Homologous Recombination Deficiency ◽  
Repair Pathways

Poly (ADP-ribose) polymerases (PARPs) play an important role in various cellular processes, such as replication, recombination, chromatin remodeling, and DNA repair. Emphasizing PARP’s role in facilitating DNA repair, the PARP pathway has been a target for cancer researchers in developing compounds which selectively target cancer cells and increase sensitivity of cancer cells to other anticancer agents, but which also leave normal cells unaffected. Since certain tumors (BRCA1/2 mutants) have deficient homologous recombination repair pathways, they depend on PARP-mediated base excision repair for survival. Thus, inhibition of PARP is a promising strategy to selectively kill cancer cells by inactivating complementary DNA repair pathways. Although PARP inhibitor therapy has predominantly targeted BRCA-mutated cancers, this review also highlights the growing conversation around PARP inhibitor treatment for non-BRCA-mutant tumors, those which exhibit BRCAness and homologous recombination deficiency. We provide an update on the field’s progress by considering PARP inhibitor mechanisms, predictive biomarkers, and clinical trials of PARP inhibitors in development. Bringing light to these findings would provide a basis for expanding the use of PARP inhibitors beyond BRCA-mutant breast tumors.

scholarly journals Identification of Cancer–associated metabolic vulnerabilities by modeling multi-objective optimality in metabolism

2019 ◽  
Vol 17 (1) ◽  
Author(s):  
Ziwei Dai ◽  
Shiyu Yang ◽  
Liyan Xu ◽  
Hongrong Hu ◽  
Kun Liao ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Cell Lines ◽  
Cancer Cell ◽  
Optimization Model ◽  
Warburg Effect ◽  
Cancer Metabolism ◽  
Metabolic Enzymes ◽  
Cancer Cell Lines ◽  
Multi Objective Optimization ◽  
Multi Objective

Abstract Background Cancer cells undergo global reprogramming of cellular metabolism to satisfy demands of energy and biomass during proliferation and metastasis. Computational modeling of genome-scale metabolic models is an effective approach for designing new therapeutics targeting dysregulated cancer metabolism by identifying metabolic enzymes crucial for satisfying metabolic goals of cancer cells, but nearly all previous studies neglect the existence of metabolic demands other than biomass synthesis and trade-offs between these contradicting metabolic demands. It is thus necessary to develop computational models covering multiple metabolic objectives to study cancer metabolism and identify novel metabolic targets. Methods We developed a multi-objective optimization model for cancer cell metabolism at genome-scale and an integrated, data-driven workflow for analyzing the Pareto optimality of this model in achieving multiple metabolic goals and identifying metabolic enzymes crucial for maintaining cancer-associated metabolic phenotypes. Using this workflow, we constructed cell line-specific models for a panel of cancer cell lines and identified lists of metabolic targets promoting or suppressing cancer cell proliferation or the Warburg Effect. The targets were then validated using knockdown and over-expression experiments in cultured cancer cell lines. Results We found that the multi-objective optimization model correctly predicted phenotypes including cell growth rates, essentiality of metabolic genes and cell line specific sensitivities to metabolic perturbations. To our surprise, metabolic enzymes promoting proliferation substantially overlapped with those suppressing the Warburg Effect, suggesting that simply targeting the overlapping enzymes may lead to complicated outcomes. We also identified lists of metabolic enzymes important for maintaining rapid proliferation or high Warburg Effect while having little effect on the other. The importance of these enzymes in cancer metabolism predicted by the model was validated by their association with cancer patient survival and knockdown and overexpression experiments in a variety of cancer cell lines. Conclusions These results confirm this multi-objective optimization model as a novel and effective approach for studying trade-off between metabolic demands of cancer cells and identifying cancer-associated metabolic vulnerabilities, and suggest novel metabolic targets for cancer treatment. Graphical abstract

Impairment of homologous recombination directed DNA repair in prostate cancer cells exposed to anchorage independence

2004 ◽  
Vol 22 (14_suppl) ◽  
pp. 9638-9638
Author(s):  
K. Reiss ◽  
J. Y. Wang ◽  
T. Ho ◽  
T. Stoklosa ◽  
T. Skorski ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Dna Repair ◽  
Homologous Recombination ◽  
Cancer Cells ◽  
Prostate Cancer Cells ◽  
Anchorage Independence

scholarly journals Genetic Recombination in Bacillus subtilis 168: Effect of ΔhelD on DNA Repair and Homologous Recombination

2001 ◽  
Vol 183 (19) ◽  
pp. 5772-5777 ◽  
Author(s):  
Begoña Carrasco ◽  
Silvia Fernández ◽  
Marie-Agnes Petit ◽  
Juan C. Alonso
Keyword(s):  
Dna Repair ◽  
Bacillus Subtilis ◽  
Homologous Recombination ◽  
Genetic Recombination ◽  
Methyl Methanesulfonate ◽  
Plasmid Transformation ◽  
Dna Damaging Agents ◽  
Bacillus Subtilis 168 ◽  
Recombination Repair ◽  
Helicase Iv

ABSTRACT The B. subtilis ΔhelD allele rendered cells proficient in transformational recombination and moderately sensitive to methyl methanesulfonate when present in an otherwise Rec+ strain. The ΔhelD allele was introduced into rec-deficient strains representative of the α (recF strain), β (addA addB), γ (recH), ɛ (ΔrecU), and ζ (ΔrecS) epistatic groups. The ΔhelDmutation increased the sensitivity to DNA-damaging agents ofaddAB, ΔrecU, and ΔrecS cells, did not affect the survival ofrecH cells, and decreased the sensitivity ofrecF cells. ΔhelD also partially suppressed the DNA repair phenotype of other mutations classified within the α epistatic group, namely the recL, ΔrecO, and recR mutations. The ΔhelD allele marginally reduced plasmid transformation (three- to sevenfold) of mutations classified within the α, β, and γ epistatic groups. Altogether, these data indicate that the loss of helicase IV might stabilize recombination repair intermediates formed in the absence of recFLOR and renderrecFLOR, addAB, andrecH cells impaired in plasmid transformation.

scholarly journals NUCKS1 promotes RAD54 activity in homologous recombination DNA repair

2020 ◽  
Vol 219 (10) ◽  
Author(s):  
David G. Maranon ◽  
Neelam Sharma ◽  
Yuxin Huang ◽  
Platon Selemenakis ◽  
Meiling Wang ◽  
...  
Keyword(s):  
Dna Repair ◽  
Homologous Recombination ◽  
Human Cells ◽  
Cyclin Dependent Kinase ◽  
Loop Formation ◽  
Multifunctional Protein ◽  
Kinase Substrate ◽  
Dna Damage Signaling ◽  
Dna Damaging Agents

NUCKS1 (nuclear ubiquitous casein kinase and cyclin-dependent kinase substrate 1) is a chromatin-associated, vertebrate-specific, and multifunctional protein with a role in DNA damage signaling and repair. Previously, we have shown that NUCKS1 helps maintain homologous recombination (HR) DNA repair in human cells and functions as a tumor suppressor in mice. However, the mechanisms by which NUCKS1 positively impacts these processes had remained unclear. Here, we show that NUCKS1 physically and functionally interacts with the DNA motor protein RAD54. Upon exposure of human cells to DNA-damaging agents, NUCKS1 controls the resolution of RAD54 foci. In unperturbed cells, NUCKS1 prevents RAD54’s inappropriate engagement with RAD51AP1. In vitro, NUCKS1 stimulates the ATPase activity of RAD54 and the RAD51–RAD54-mediated strand invasion step during displacement loop formation. Taken together, our data demonstrate that the NUCKS1 protein is an important new regulator of the spatiotemporal events in HR.

scholarly journals Selective killing of homologous recombination-deficient cancer cell lines by inhibitors of the RPA:RAD52 protein-protein interaction

PLoS ONE ◽  
2021 ◽  
Vol 16 (3) ◽  
pp. e0248941
Author(s):  
Mona Al-Mugotir ◽  
Jeffrey J. Lovelace ◽  
Joseph George ◽  
Mika Bessho ◽  
Dhananjaya Pal ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Homologous Recombination ◽  
Cancer Cells ◽  
Cell Lines ◽  
Cancer Cell ◽  
Protein Interaction ◽  
Ovarian Cancer Cells ◽  
Protein Protein Interaction ◽  
Approved Drugs ◽  
Fda Approved Drugs

Synthetic lethality is a successful strategy employed to develop selective chemotherapeutics against cancer cells. Inactivation of RAD52 is synthetically lethal to homologous recombination (HR) deficient cancer cell lines. Replication protein A (RPA) recruits RAD52 to repair sites, and the formation of this protein-protein complex is critical for RAD52 activity. To discover small molecules that inhibit the RPA:RAD52 protein-protein interaction (PPI), we screened chemical libraries with our newly developed Fluorescence-based protein-protein Interaction Assay (FluorIA). Eleven compounds were identified, including FDA-approved drugs (quinacrine, mitoxantrone, and doxorubicin). The FluorIA was used to rank the compounds by their ability to inhibit the RPA:RAD52 PPI and showed mitoxantrone and doxorubicin to be the most effective. Initial studies using the three FDA-approved drugs showed selective killing of BRCA1-mutated breast cancer cells (HCC1937), BRCA2-mutated ovarian cancer cells (PE01), and BRCA1-mutated ovarian cancer cells (UWB1.289). It was noteworthy that selective killing was seen in cells known to be resistant to PARP inhibitors (HCC1937 and UWB1 SYr13). A cell-based double-strand break (DSB) repair assay indicated that mitoxantrone significantly suppressed RAD52-dependent single-strand annealing (SSA) and mitoxantrone treatment disrupted the RPA:RAD52 PPI in cells. Furthermore, mitoxantrone reduced radiation-induced foci-formation of RAD52 with no significant activity against RAD51 foci formation. The results indicate that the RPA:RAD52 PPI could be a therapeutic target for HR-deficient cancers. These data also suggest that RAD52 is one of the targets of mitoxantrone and related compounds.

scholarly journals Sublethal concentrations of 17-AAG suppress homologous recombination DNA repair and enhance sensitivity to carboplatin and olaparib in HR proficient ovarian cancer cells

Oncotarget ◽  
2014 ◽  
Vol 5 (9) ◽  
pp. 2678-2687 ◽  
Author(s):  
Young Eun Choi ◽  
Chiara Battelli ◽  
Jacqueline Watson ◽  
Joyce Liu ◽  
Jennifer Curtis ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Dna Repair ◽  
Homologous Recombination ◽  
Cancer Cells ◽  
Ovarian Cancer Cells ◽  
Sublethal Concentrations
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