scholarly journals VRK1 is a Paralog Synthetic Lethal Target in VRK2-methylated Glioblastoma

2022 ◽  
Author(s):  
Julie A Shields ◽  
Samuel R Meier ◽  
Madhavi Bandi ◽  
Maria Dam Ferdinez ◽  
Justin L Engel ◽  
...  
Keyword(s):  
Kinase Activity ◽  
Genetic Interaction ◽  
Synthetic Lethality ◽  
Cancer Therapeutics ◽  
Tumor Growth Inhibition ◽  
Synthetic Lethal Interaction ◽  
Synthetic Lethal ◽  
Aggressive Cancer ◽  
Nuclear Envelope Formation ◽  
Redundant Functions

Synthetic lethality - a genetic interaction that results in cell death when two genetic deficiencies co-occur but not when either deficiency occurs alone - can be co-opted for cancer therapeutics. A pair of paralog genes is among the most straightforward synthetic lethal interaction by virtue of their redundant functions. Here we demonstrate a paralog-based synthetic lethality by targeting Vaccinia-Related Kinase 1 (VRK1) in Vaccinia-Related Kinase 2 (VRK2)-methylated glioblastoma (GBM). VRK2 is silenced by promoter methylation in approximately two-thirds of GBM, an aggressive cancer with few available targeted therapies. Genetic knockdown of VRK1 in VRK2-null or VRK2-methylated cells results in decreased activity of the downstream substrate Barrier to Autointegration Factor (BAF), a regulator of post-mitotic nuclear envelope formation. VRK1 knockdown, and thus reduced BAF activity, causes nuclear lobulation, blebbing and micronucleation, which subsequently results in G2/M arrest and DNA damage. The VRK1-VRK2 synthetic lethal interaction is dependent on VRK1 kinase activity and is rescued by ectopic VRK2 expression. Knockdown of VRK1 leads to robust tumor growth inhibition in VRK2-methylated GBM xenografts. These results indicate that inhibiting VRK1 kinase activity could be a viable therapeutic strategy in VRK2-methylated GBM.

scholarly journals Predicting synthetic lethal interactions in human cancers using graph regularized self-representative matrix factorization

2019 ◽  
Vol 20 (S19) ◽  
Author(s):  
Jiang Huang ◽  
Min Wu ◽  
Fan Lu ◽  
Le Ou-Yang ◽  
Zexuan Zhu
Keyword(s):  
Matrix Factorization ◽  
Drug Targets ◽  
Synthetic Lethality ◽  
Cancer Therapeutics ◽  
The Self ◽  
Interaction Data ◽  
Synthetic Lethal Interaction ◽  
Synthetic Lethal ◽  
Interaction Prediction ◽  
Synthetic Lethal Interactions

Abstract Background Synthetic lethality has attracted a lot of attentions in cancer therapeutics due to its utility in identifying new anticancer drug targets. Identifying synthetic lethal (SL) interactions is the key step towards the exploration of synthetic lethality in cancer treatment. However, biological experiments are faced with many challenges when identifying synthetic lethal interactions. Thus, it is necessary to develop computational methods which could serve as useful complements to biological experiments. Results In this paper, we propose a novel graph regularized self-representative matrix factorization (GRSMF) algorithm for synthetic lethal interaction prediction. GRSMF first learns the self-representations from the known SL interactions and further integrates the functional similarities among genes derived from Gene Ontology (GO). It can then effectively predict potential SL interactions by leveraging the information provided by known SL interactions and functional annotations of genes. Extensive experiments on the synthetic lethal interaction data downloaded from SynLethDB database demonstrate the superiority of our GRSMF in predicting potential synthetic lethal interactions, compared with other competing methods. Moreover, case studies of novel interactions are conducted in this paper for further evaluating the effectiveness of GRSMF in synthetic lethal interaction prediction. Conclusions In this paper, we demonstrate that by adaptively exploiting the self-representation of original SL interaction data, and utilizing functional similarities among genes to enhance the learning of self-representation matrix, our GRSMF could predict potential SL interactions more accurately than other state-of-the-art SL interaction prediction methods.

scholarly journals Using Yeast Synthetic Lethality To Inform Drug Combination for Malaria

2018 ◽  
Vol 62 (4) ◽  
Author(s):  
Suvitha Subramaniam ◽  
Christoph D. Schmid ◽  
Xue Li Guan ◽  
Pascal Mäser
Keyword(s):  
Plasmodium Falciparum ◽  
Drug Combination ◽  
Synthetic Lethality ◽  
Drug Combinations ◽  
Synthetic Lethal Interaction ◽  
Content Type ◽  
Synthetic Lethal ◽  
Gene Pairs ◽  
Phosphatidylinositol 4

ABSTRACT Combinatorial chemotherapy is necessary for the treatment of malaria. However, finding a suitable partner drug for a new candidate is challenging. Here we develop an algorithm that identifies all of the gene pairs of Plasmodium falciparum that possess orthologues in yeast that have a synthetic lethal interaction but are absent in humans. This suggests new options for drug combinations, particularly for inhibitors of targets such as P. falciparum calcineurin, cation ATPase 4, or phosphatidylinositol 4-kinase.

A Screen for Dynein Synthetic Lethals in Aspergillus nidulans Identifies Spindle Assembly Checkpoint Genes and Other Genes Involved in Mitosis

Genetics ◽  
1998 ◽  
Vol 149 (1) ◽  
pp. 101-116
Author(s):  
Vladimir P Efimov ◽  
N Ronald Morris
Keyword(s):  
Aspergillus Nidulans ◽  
Spindle Assembly Checkpoint ◽  
Genetic Interaction ◽  
Synthetic Lethality ◽  
Spindle Assembly ◽  
Nuclear Migration ◽  
Cytoplasmic Dynein ◽  
Vesicle Transport ◽  
Synthetic Lethal ◽  
Checkpoint Genes

Abstract Cytoplasmic dynein is a ubiquitously expressed microtubule motor involved in vesicle transport, mitosis, nuclear migration, and spindle orientation. In the filamentous fungus Aspergillus nidulans, inactivation of cytoplasmic dynein, although not lethal, severely impairs nuclear migration. The role of dynein in mitosis and vesicle transport in this organism is unclear. To investigate the complete range of dynein function in A. nidulans, we searched for synthetic lethal mutations that significantly reduced growth in the absence of dynein but had little effect on their own. We isolated 19 sld (synthetic lethality without dynein) mutations in nine different genes. Mutations in two genes exacerbate the nuclear migration defect seen in the absence of dynein. Mutations in six other genes, including sldA and sldB, show a strong synthetic lethal interaction with a mutation in the mitotic kinesin bimC and, thus, are likely to play a role in mitosis. Mutations in sldA and sldB also confer hypersensitivity to the microtubule-destabilizing drug benomyl. sldA and sldB were cloned by complementation of their mutant phenotypes using an A. nidulans autonomously replicating vector. Sequencing revealed homology to the spindle assembly checkpoint genes BUB1 and BUB3 from Saccharomyces cerevisiae. Genetic interaction between dynein and spindle assembly checkpoint genes, as well as other mitotic genes, indicates that A. nidulans dynein plays a role in mitosis. We suggest a model for dynein motor action in A. nidulans that can explain dynein involvement in both mitosis and nuclear distribution.

scholarly journals A high-content screen identifies the vulnerability of MYC-overexpressing cells to dimethylfasudil

2019 ◽  
Author(s):  
Jing Zhang ◽  
Shenqiu Zhang ◽  
Qiong Shi ◽  
Thaddeus D. Allen ◽  
Fengming You ◽  
...  
Keyword(s):  
Cell Lines ◽  
Synthetic Lethality ◽  
Human Cancer ◽  
Lethal Effect ◽  
Reversible Inhibitor ◽  
Synthetic Lethal Interaction ◽  
Synthetic Lethal ◽  
Human Cancer Cell Lines ◽  
Direct Targeting ◽  
Approved Drugs

AbstractA synthetic lethal effect arises when a cancer-associated change introduces a unique vulnerability to cancer cells that makes them unusually susceptible to a drug’s inhibitory activity. The synthetic lethal approach is attractive because it enables targeting of cancers harboring specific genomic alterations, the products of which may have proven refractory to direct targeting. An example is cancer driven by overexpression of MYC. Here, we conducted a high-content screen for compounds that are synthetic lethal to elevated MYC using a small-molecule library to identify compounds that are closely related to, or are themselves, regulatory-approved drugs. The screen identified dimethylfasudil, a potent and reversible inhibitor of Rho-associated kinases ROCK1 and ROCK2. Close analogs of dimethylfasudil are used clinically to treat neurologic and cardiovascular disorders. The synthetic lethal interaction was conserved in rodent and human cell lines and could be observed with activation of either MYC or its paralog MYCN. The synthetic lethality seems specific to MYC overexpressing cells as it could not be substituted by a variety of oncogenic manipulations and synthetic lethality was diminished by RNAi-mediated depletion of MYC in human cancer cell lines. Collectively, these data support investigation of the use of dimethylfasudil as a drug that is synthetic lethal for malignancies that specifically overexpress MYC.Significance StatementSynthetic lethal targeting of tumors overexpressing MYC holds promise for attacking aggressive malignancies. Here we describe a synthetic lethal interaction between dimethylfasudil and overexpression of MYC. Uniquely, this novel synthetic lethal interaction points toward an opportunity for synthetic lethality with a molecule likely to harbor favorable drug-like properties that enable systemic use.

scholarly journals Uncovering cancer vulnerabilities by machine learning prediction of synthetic lethality

2021 ◽  
Vol 20 (1) ◽  
Author(s):  
Salvatore Benfatto ◽  
Özdemirhan Serçin ◽  
Francesca R. Dejure ◽  
Amir Abdollahi ◽  
Frank T. Zenke ◽  
...  
Keyword(s):  
Machine Learning ◽  
Cancer Genomics ◽  
Genetic Interaction ◽  
Synthetic Lethality ◽  
Interacting Protein ◽  
Synthetic Lethal ◽  
Damage Repair ◽  
Genome Wide ◽  
Machine Learning Approach ◽  
Transcriptomics Data

Abstract Background Synthetic lethality describes a genetic interaction between two perturbations, leading to cell death, whereas neither event alone has a significant effect on cell viability. This concept can be exploited to specifically target tumor cells. CRISPR viability screens have been widely employed to identify cancer vulnerabilities. However, an approach to systematically infer genetic interactions from viability screens is missing. Methods Here we describe PAn-canceR Inferred Synthetic lethalities (PARIS), a machine learning approach to identify cancer vulnerabilities. PARIS predicts synthetic lethal (SL) interactions by combining CRISPR viability screens with genomics and transcriptomics data across hundreds of cancer cell lines profiled within the Cancer Dependency Map. Results Using PARIS, we predicted 15 high confidence SL interactions within 549 DNA damage repair (DDR) genes. We show experimental validation of an SL interaction between the tumor suppressor CDKN2A, thymidine phosphorylase (TYMP) and the thymidylate synthase (TYMS), which may allow stratifying patients for treatment with TYMS inhibitors. Using genome-wide mapping of SL interactions for DDR genes, we unraveled a dependency between the aldehyde dehydrogenase ALDH2 and the BRCA-interacting protein BRIP1. Our results suggest BRIP1 as a potential therapeutic target in ~ 30% of all tumors, which express low levels of ALDH2. Conclusions PARIS is an unbiased, scalable and easy to adapt platform to identify SL interactions that should aid in improving cancer therapy with increased availability of cancer genomics data.

scholarly journals WRN Helicase is a Synthetic Lethal Target in Microsatellite Unstable Cancers

2018 ◽  
Author(s):  
Edmond Chan ◽  
Tsukasa Shibue ◽  
James McFarland ◽  
Benjamin Gaeta ◽  
Justine McPartlan ◽  
...  
Keyword(s):  
Dna Repair ◽  
Cell Lines ◽  
Large Scale ◽  
Synthetic Lethality ◽  
Cancer Therapeutics ◽  
Dna Helicase ◽  
Dna Breaks ◽  
Synthetic Lethal ◽  
Dna Mismatch ◽  
Double Strand Dna Breaks

Synthetic lethality, an interaction whereby the co-occurrence of two or more genetic events lead to cell death but one event alone does not, can be exploited to develop novel cancer therapeutics. DNA repair processes represent attractive synthetic lethal targets since many cancers exhibit an impaired DNA repair pathway, which can lead these cells to become dependent on specific repair proteins. The success of poly (ADP-ribose) polymerase 1 (PARP-1) inhibitors in homologous recombination-deficient cancers highlights the potential of this approach in clinical oncology. Hypothesizing that other DNA repair defects would give rise to alternative synthetic lethal relationships, we asked if there are specific dependencies in cancers with microsatellite instability (MSI), which results from impaired DNA mismatch repair (MMR). Here we analyzed data from large-scale CRISPR/Cas9 knockout and RNA interference (RNAi) silencing screens and found that the RecQ DNA helicase was selectively essential in MSI cell lines, yet dispensable in microsatellite stable (MSS) cell lines. WRN depletion induced double-strand DNA breaks and promoted apoptosis and cell cycle arrest selectively in MSI models. MSI cancer models specifically required the helicase activity, but not the exonuclease activity of WRN. These findings expose WRN as a synthetic lethal vulnerability and promising drug target in MSI cancers.

scholarly journals Synthetic Lethality of Wnt Pathway Activation and Asparaginase in Drug-Resistant Acute Leukemias

2018 ◽  
Author(s):  
Laura Hinze ◽  
Maren Pfirrmann ◽  
Salmaan Karim ◽  
James Degar ◽  
Connor McGuckin ◽  
...  
Keyword(s):  
Acute Leukemia ◽  
Wnt Pathway ◽  
Synthetic Lethality ◽  
Therapeutic Index ◽  
Drug Resistant ◽  
Synthetic Lethal Interaction ◽  
Acute Leukemias ◽  
Synthetic Lethal ◽  
Pathway Activation ◽  
A Genome

SUMMARYResistance to asparaginase, an antileukemic enzyme that depletes asparagine, is a common clinical problem. Using a genome-wide CRISPR/Cas9 screen, we found a synthetic lethal interaction between Wnt pathway activation and asparaginase in acute leukemias resistant to this enzyme. Wnt pathway activation induced asparaginase sensitivity in distinct treatment-resistant subtypes of acute leukemia, including T-lymphoblastic, hypodiploid B-lymphoblastic, and acute myeloid leukemias, but not in normal hematopoietic progenitors. Sensitization to asparaginase was mediated by Wnt-dependent stabilization of proteins (Wnt/STOP), which inhibits GSK3-dependent protein ubiquitination and degradation. Inhibiting the alpha isoform of GSK3 phenocopied this effect, and pharmacologic GSK3α inhibition profoundly sensitized drug-resistant leukemias to asparaginase. Our findings provide a molecular rationale for activation of Wnt/STOP signaling to improve the therapeutic index of asparaginase.SIGNIFICANCEThe intensification of asparaginase-based therapy has improved outcomes for several subtypes of acute leukemia, but the development of treatment resistance has a poor prognosis. We hypothesized, from the concept of synthetic lethality, that gain-of-fitness alterations in drug-resistant cells had conferred a survival advantage that could be exploited therapeutically. We found a synthetic lethal interaction between activation of Wnt-dependent stabilization of proteins (Wnt/STOP) and asparaginase in acute leukemias resistant to this enzyme. Inhibition of the alpha isoform of GSK3 was sufficient to phenocopy this effect, and the combination of GSK3α-selective inhibitors and asparaginase had marked therapeutic activity against leukemias resistant to monotherapy with either agent. These data indicate that drug-drug synthetic lethal interactions can improve the therapeutic index of cancer therapy.

scholarly journals Paralogous synthetic lethality underlies genetic dependencies of the cancer-mutated gene STAG2

2021 ◽  
Vol 4 (11) ◽  
pp. e202101083
Author(s):  
Melanie L Bailey ◽  
David Tieu ◽  
Andrea Habsid ◽  
Amy Hin Yan Tong ◽  
Katherine Chan ◽  
...  
Keyword(s):  
Genetic Interaction ◽  
Synthetic Lethality ◽  
Regulatory Gene ◽  
Chromosome Instability ◽  
Genetic Interactions ◽  
Complex Nature ◽  
Whole Genome ◽  
Cohesin Complex ◽  
Synthetic Lethal ◽  
Cancer Types

STAG2, a component of the mitotically essential cohesin complex, is highly mutated in several different tumour types, including glioblastoma and bladder cancer. Whereas cohesin has roles in many cancer-related pathways, such as chromosome instability, DNA repair and gene expression, the complex nature of cohesin function has made it difficult to determine how STAG2 loss might either promote tumorigenesis or be leveraged therapeutically across divergent cancer types. Here, we have performed whole-genome CRISPR-Cas9 screens for STAG2-dependent genetic interactions in three distinct cellular backgrounds. Surprisingly, STAG1, the paralog of STAG2, was the only negative genetic interaction that was shared across all three backgrounds. We also uncovered a paralogous synthetic lethal mechanism behind a genetic interaction between STAG2 and the iron regulatory gene IREB2. Finally, investigation of an unusually strong context-dependent genetic interaction in HAP1 cells revealed factors that could be important for alleviating cohesin loading stress. Together, our results reveal new facets of STAG2 and cohesin function across a variety of genetic contexts.

scholarly journals Integration of pathway, cellular and genetic context reveals principles of synthetic lethality that affect reproducibility

2019 ◽  
Author(s):  
Angel A. Ku ◽  
Sameera Kongara ◽  
Hsien-Ming Hu ◽  
Xin Zhao ◽  
Di Wu ◽  
...  
Keyword(s):  
Genetic Interaction ◽  
Synthetic Lethality ◽  
Synthetic Lethal ◽  
Testing Framework ◽  
Gene Level ◽  
Cancer Mutations ◽  
Experimental Approaches ◽  
Interaction Map ◽  
Mutant Cells ◽  
Genetic Context

ABSTRACTSynthetic lethal screens have the potential to identify new vulnerabilities incurred by specific cancer mutations but have been hindered by lack of agreement between studies. Using KRAS as a model, we identified that published synthetic lethal screens significantly overlap at the pathway rather than gene level. Analysis of pathways encoded as protein networks identified synthetic lethal candidates that were more reproducible than those previously reported. Lack of overlap likely stems from biological rather than technical limitations as most synthetic lethal phenotypes were strongly modulated by changes in cellular conditions or genetic context, the latter determined using a pairwise genetic interaction map that identified numerous interactions that suppress synthetic lethal effects. Accounting for pathway, cellular and genetic context nominates a DNA repair dependency in KRAS-mutant cells, mediated by a network containing BRCA1. We provide evidence for why most reported synthetic lethals are not reproducible which is addressable using a multi-faceted testing framework.STATEMENT OF SIGNIFICANCESynthetic lethal screens have the power to identify new targets in cancer, although have thus far come up short of expectation. We use computational and experimental approaches to delineate principles for identifying robust synthetic lethal targets that could aid in the development of effective new therapeutic strategies for genetically defined cancers.

scholarly journals Discovery of synthetic lethal and tumor suppressive paralog pairs in the human genome

2020 ◽  
Author(s):  
Phoebe C. R. Parrish ◽  
James D. Thomas ◽  
Shriya Kamlapurkar ◽  
Austin Gabel ◽  
Robert K. Bradley ◽  
...  
Keyword(s):  
Drug Targets ◽  
Genetic Interaction ◽  
Synthetic Lethality ◽  
Essential Gene ◽  
Single Gene ◽  
Gene Families ◽  
Blind Spot ◽  
List Type ◽  
Double Knockout ◽  
Synthetic Lethal

AbstractCRISPR knockout screens have accelerated the discovery of important cancer genetic dependencies. However, traditional CRISPR-Cas9 screens are limited in their ability to assay the function of redundant or duplicated genes. Paralogs in multi-gene families constitute two-thirds of the protein-coding genome, so this blind spot is the rule, not the exception. To overcome the limitations of single gene CRISPR knockout screens, we developed paired guide RNAs for Paralog gENetic interaction mapping (pgPEN), a pooled CRISPR/Cas9 approach which targets over a thousand duplicated human paralogs in single knockout and double knockout configurations. We applied pgPEN to two cell lineages and discovered that over 10% of human paralogs exhibit synthetic lethality in at least one cellular context. We recovered known synthetic lethal paralogs such as MAP2K1/MAP2K2, important drug targets such as CDK4/CDK6, and numerous other synthetic lethal pairs such as CCNL1/CCNL2. In addition, we identified ten tumor suppressive paralog pairs whose compound loss promotes cell growth. These findings identify a large number of previously unidentified essential gene families and nominate new druggable targets for oncology drug discovery.HighlightsComprehensive genetic interaction mapping of 1,030 human duplicated paralogs using a dual targeting CRISPR/Cas9 approachDuplicated paralogs are highly enriched for genetic interactionsSynthetic lethal paralogs include CCNL1/CCNL2, CDK4/CDK6, and GSK3A/GSK3BTumor suppressor paralog pairs include CDKN2A/CDKN2B and FBXO25/FBXO32

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