scholarly journals STAG1 vulnerabilities for exploiting cohesin synthetic lethality in STAG2-deficient cancers

2020 ◽  
Vol 3 (7) ◽  
pp. e202000725
Author(s):  
Petra van der Lelij ◽  
Joseph A Newman ◽  
Simone Lieb ◽  
Julian Jude ◽  
Vittorio Katis ◽  
...  
Keyword(s):  
Synthetic Lethality ◽  
Wild Type ◽  
Synthetic Lethal ◽  
X Ray ◽  
X Ray Crystallography ◽  
Chemical Genetic ◽  
Biochemical Assays ◽  
Genome Wide ◽  
Chromatid Cohesion ◽  
Cohesin Subunit

The cohesin subunit STAG2 has emerged as a recurrently inactivated tumor suppressor in human cancers. Using candidate approaches, recent studies have revealed a synthetic lethal interaction between STAG2 and its paralog STAG1. To systematically probe genetic vulnerabilities in the absence of STAG2, we have performed genome-wide CRISPR screens in isogenic cell lines and identified STAG1 as the most prominent and selective dependency of STAG2-deficient cells. Using an inducible degron system, we show that chemical genetic degradation of STAG1 protein results in the loss of sister chromatid cohesion and rapid cell death in STAG2-deficient cells, while sparing STAG2–wild-type cells. Biochemical assays and X-ray crystallography identify STAG1 regions that interact with the RAD21 subunit of the cohesin complex. STAG1 mutations that abrogate this interaction selectively compromise the viability of STAG2-deficient cells. Our work highlights the degradation of STAG1 and inhibition of its interaction with RAD21 as promising therapeutic strategies. These findings lay the groundwork for the development of STAG1-directed small molecules to exploit synthetic lethality in STAG2-mutated tumors.

scholarly journals Synthetic lethality between the cohesin subunits STAG1 and STAG2 in diverse cancer contexts

2017 ◽  
Author(s):  
Petra van der Lelij ◽  
Simone Lieb ◽  
Julian Jude ◽  
Gordana Wutz ◽  
Catarina P. Santos ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Sister Chromatid ◽  
Synthetic Lethality ◽  
Sister Chromatid Cohesion ◽  
Cohesin Complex ◽  
Wild Type ◽  
Synthetic Lethal ◽  
Recurrent Mutations ◽  
Wide Range ◽  
Chromatid Cohesion

AbstractRecent genome analyses have identified recurrent mutations in the cohesin complex in a wide range of human cancers. Here we demonstrate that the most frequently mutated subunit of the cohesin complex, STAG2, displays a strong synthetic lethal interaction with its paralog STAG1. Mechanistically, STAG1 loss abrogates sister chromatid cohesion in STAG2 mutated but not in wild-type cells leading to mitotic catastrophe, defective cell division and apoptosis. STAG1 inactivation inhibits the proliferation of STAG2 mutated but not wild-type bladder cancer and Ewing sarcoma cell lines. Restoration of STAG2 expression in a mutated bladder cancer model alleviates the dependency on STAG1. Thus, STAG1 and STAG2 support sister chromatid cohesion to redundantly ensure cell survival. STAG1 represents a vulnerability of cancer cells carrying mutations in the major emerging tumor suppressor STAG2 across different cancer contexts. Exploiting synthetic lethal interactions to target recurrent cohesin mutations in cancer, e.g. by inhibiting STAG1, holds the promise for the development of selective therapeutics.

scholarly journals Synthetic lethality between the cohesin subunits STAG1 and STAG2 in diverse cancer contexts

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Petra van der Lelij ◽  
Simone Lieb ◽  
Julian Jude ◽  
Gordana Wutz ◽  
Catarina P Santos ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Sister Chromatid ◽  
Synthetic Lethality ◽  
Sister Chromatid Cohesion ◽  
Cohesin Complex ◽  
Wild Type ◽  
Synthetic Lethal ◽  
Recurrent Mutations ◽  
Wide Range ◽  
Chromatid Cohesion

Recent genome analyses have identified recurrent mutations in the cohesin complex in a wide range of human cancers. Here we demonstrate that the most frequently mutated subunit of the cohesin complex, STAG2, displays a strong synthetic lethal interaction with its paralog STAG1. Mechanistically, STAG1 loss abrogates sister chromatid cohesion in STAG2 mutated but not in wild-type cells leading to mitotic catastrophe, defective cell division and apoptosis. STAG1 inactivation inhibits the proliferation of STAG2 mutated but not wild-type bladder cancer and Ewing sarcoma cell lines. Restoration of STAG2 expression in a mutated bladder cancer model alleviates the dependency on STAG1. Thus, STAG1 and STAG2 support sister chromatid cohesion to redundantly ensure cell survival. STAG1 represents a vulnerability of cancer cells carrying mutations in the major emerging tumor suppressor STAG2 across different cancer contexts. Exploiting synthetic lethal interactions to target recurrent cohesin mutations in cancer, e.g. by inhibiting STAG1, holds the promise for the development of selective therapeutics.

scholarly journals PHF13 is a molecular reader and transcriptional co-regulator of H3K4me2/3

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Ho-Ryun Chung ◽  
Chao Xu ◽  
Alisa Fuchs ◽  
Andreas Mund ◽  
Martin Lange ◽  
...  
Keyword(s):  
Dna Damage Response ◽  
Size Exclusion ◽  
X Ray ◽  
Chip Sequencing ◽  
X Ray Crystallography ◽  
Genome Wide ◽  
Damage Response ◽  
Exclusion Chromatography ◽  
Insight Into ◽  
Binding Cell

PHF13 is a chromatin affiliated protein with a functional role in differentiation, cell division, DNA damage response and higher chromatin order. To gain insight into PHF13's ability to modulate these processes, we elucidate the mechanisms targeting PHF13 to chromatin, its genome wide localization and its molecular chromatin context. Size exclusion chromatography, mass spectrometry, X-ray crystallography and ChIP sequencing demonstrate that PHF13 binds chromatin in a multivalent fashion via direct interactions with H3K4me2/3 and DNA, and indirectly via interactions with PRC2 and RNA PolII. Furthermore, PHF13 depletion disrupted the interactions between PRC2, RNA PolII S5P, H3K4me3 and H3K27me3 and resulted in the up and down regulation of genes functionally enriched in transcriptional regulation, DNA binding, cell cycle, differentiation and chromatin organization. Together our findings argue that PHF13 is an H3K4me2/3 molecular reader and transcriptional co-regulator, affording it the ability to impact different chromatin processes.

scholarly journals Cohesin mutations are synthetic lethal with stimulation of WNT signaling

2020 ◽  
Author(s):  
Chue Vin Chin ◽  
Jisha Antony ◽  
Sarada Ketharnathan ◽  
Gregory Gimenez ◽  
Kate M. Parsons ◽  
...  
Keyword(s):  
Wnt Signaling ◽  
Synthetic Lethality ◽  
Mcf10a Cell ◽  
Synthetic Lethal ◽  
Deletion Mutations ◽  
Damage Repair ◽  
Genes Encoding ◽  
Cohesin Subunit ◽  
Mutant Cells ◽  
Gsk3 Inhibitor

AbstractMutations in genes encoding subunits of the cohesin complex are common in several cancers, but may also expose druggable vulnerabilities. We generated isogenic MCF10A cell lines with deletion mutations of genes encoding cohesin subunits SMC3, RAD21 and STAG2 and screened for synthetic lethality with 3,009 FDA-approved compounds. The screen identified several compounds that interfere with transcription, DNA damage repair and the cell cycle. Unexpectedly, one of the top ‘hits’ was a GSK3 inhibitor, an agonist of Wnt signaling. We show that sensitivity to GSK3 inhibition is likely due to stabilization of β-catenin in cohesin mutant cells, and that Wnt-responsive gene expression is highly sensitized in STAG2-mutant CMK leukemia cells. Moreover, Wnt activity is enhanced in zebrafish mutant for cohesin subunit rad21. Our results suggest that cohesin mutations could progress oncogenesis by enhancing Wnt signaling, and that targeting the Wnt pathway may represent a novel therapeutic strategy for cohesin mutant cancers.

scholarly journals Genome-wide screen of Saccharomyces cerevisiae null allele strains identifies genes involved in selenomethionine resistance

2008 ◽  
Vol 105 (46) ◽  
pp. 17682-17687 ◽  
Author(s):  
Jessica Bockhorn ◽  
Bharvi Balar ◽  
Dongming He ◽  
Eden Seitomer ◽  
Paul R. Copeland ◽  
...  
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Null Allele ◽  
Cost Effective ◽  
Anomalous Dispersion ◽  
Gene Encoding ◽  
X Ray ◽  
X Ray Crystallography ◽  
Genome Wide ◽  
Cost Effective Method ◽  
Strain Collection

Selenomethionine (SeMet) is a potentially toxic amino acid, and yet it is a valuable tool in the preparation of labeled proteins for multiwavelength anomalous dispersion or single-wavelength anomalous dispersion phasing in X-ray crystallography. The mechanism by which high levels of SeMet exhibits its toxic effects in eukaryotic cells is not fully understood. Attempts to use Saccharomyces cerevisiae for the preparation of fully substituted SeMet proteins for X-ray crystallography have been limited. A screen of the viable S. cerevisiae haploid null allele strain collection for resistance to SeMet was performed. Deletion of the CYS3 gene encoding cystathionine gamma-lyase resulted in the highest resistance to SeMet. In addition, deletion of SSN2 resulted in both increased resistance to SeMet as well as reduced levels of Cys3p. A methionine auxotrophic strain lacking CYS3 was able to grow in media with SeMet as the only source of Met, achieving essentially 100% occupancy in total proteins. The CYS3 deletion strain provides advantages for an easy and cost-effective method to prepare SeMet-substituted protein in yeast and perhaps other eukaryotic systems.

scholarly journals Targeting mutant p53 for cancer therapy: direct and indirect strategies

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Jiahao Hu ◽  
Jiasheng Cao ◽  
Win Topatana ◽  
Sarun Juengpanich ◽  
Shijie Li ◽  
...  
Keyword(s):  
Noncoding Rna ◽  
Synthetic Lethality ◽  
Noncoding Rnas ◽  
Research Progress ◽  
Mutant P53 ◽  
Wild Type ◽  
Synthetic Lethal ◽  
Therapeutic Benefits ◽  
Synthetic Lethal Interactions ◽  
Wild Type P53

AbstractTP53 is a critical tumor-suppressor gene that is mutated in more than half of all human cancers. Mutations in TP53 not only impair its antitumor activity, but also confer mutant p53 protein oncogenic properties. The p53-targeted therapy approach began with the identification of compounds capable of restoring/reactivating wild-type p53 functions or eliminating mutant p53. Treatments that directly target mutant p53 are extremely structure and drug-species-dependent. Due to the mutation of wild-type p53, multiple survival pathways that are normally maintained by wild-type p53 are disrupted, necessitating the activation of compensatory genes or pathways to promote cancer cell survival. Additionally, because the oncogenic functions of mutant p53 contribute to cancer proliferation and metastasis, targeting the signaling pathways altered by p53 mutation appears to be an attractive strategy. Synthetic lethality implies that while disruption of either gene alone is permissible among two genes with synthetic lethal interactions, complete disruption of both genes results in cell death. Thus, rather than directly targeting p53, exploiting mutant p53 synthetic lethal genes may provide additional therapeutic benefits. Additionally, research progress on the functions of noncoding RNAs has made it clear that disrupting noncoding RNA networks has a favorable antitumor effect, supporting the hypothesis that targeting noncoding RNAs may have potential synthetic lethal effects in cancers with p53 mutations. The purpose of this review is to discuss treatments for cancers with mutant p53 that focus on directly targeting mutant p53, restoring wild-type functions, and exploiting synthetic lethal interactions with mutant p53. Additionally, the possibility of noncoding RNAs acting as synthetic lethal targets for mutant p53 will be discussed.

scholarly journals Hardwired synthetic lethality within the cohesin complex in human cancer cells

2017 ◽  
Author(s):  
Petra van der Lelij ◽  
Simone Lieb ◽  
Julian Jude ◽  
Gordana Wutz ◽  
Catarina P. Santos ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Cancer Cells ◽  
Sister Chromatid ◽  
Sister Chromatid Cohesion ◽  
Cohesin Complex ◽  
Wild Type ◽  
Synthetic Lethal ◽  
Recurrent Mutations ◽  
Wide Range ◽  
Chromatid Cohesion

AbstractRecent genome analyses have identified recurrent mutations in the cohesin complex in a wide range of human cancers. Here we demonstrate that the most frequently mutated subunit of the cohesin complex, STAG2, displays a strong synthetic lethal interaction with its paralog STAG1. Mechanistically, STAG1 loss abrogates sister chromatid cohesion in STAG2 mutated but not in wild-type cells leading to mitotic catastrophe, defective cell division and apoptosis. STAG1 inactivation inhibits the proliferation of STAG2 mutated but not wild-type bladder cancer and Ewing sarcoma cell lines. Restoration of STAG2 expression in a mutated bladder cancer model alleviates the dependency on STAG1. Thus, STAG1 and STAG2 act redundantly to support sister chromatid cohesion and cell survival. STAG1 represents a hardwired, context independent vulnerability of cancer cells carrying mutations in the major emerging tumor suppressor STAG2. Exploiting synthetic lethal interactions to target recurrent cohesin mutations in cancer, e.g. by inhibiting STAG1, holds the promise for the development of selective therapeutics.

scholarly journals Attacking COVID-19 Progression using Multi-Drug Therapy for Synergetic Target Engagement

2020 ◽  
Author(s):  
Mathew Coban ◽  
Juliet Morrison ◽  
William Freeman ◽  
Evette S. Radisky ◽  
Karine Le Roch ◽  
...  
Keyword(s):  
Infectious Disease ◽  
Harvard Medical School ◽  
Target Engagement ◽  
Live Virus ◽  
X Ray ◽  
X Ray Crystallography ◽  
Biochemical Assays ◽  
Compound Screening ◽  
Chemical Studies ◽  
Virus Screening

We are presenting our on going studies with inhibitory research on Tmprss2, S-protein:Ace2, and 3CLpro using compound screening coupled with X-ray crystallography, molecular modeling, live virus screening using host human cells (BSL3 facility at UC Center for Infectious Disease and Vector Research, and organ-on-a-chip at Harvard Medical School for safety profiling before proceeding to animal models with InVivo BioSystems for ADMET.<br><div>We have derived a useful chemical toolkit of 350 compounds for the community to study with biochemical assays and other biophysical-chemical studies that will prove useful in searching for optimal inhibitors of these targets to find suitable pharmacophores for blocking each of these enzyme's activities -- that would be beneficial for human health. Our past successes with these methodologies have resulted in over 28 patents, 11 technologies and two startup companies. </div>

scholarly journals Inhibition of miR-1193 leads to synthetic lethality in glioblastoma multiforme cells deficient of DNA-PKcs

2020 ◽  
Vol 11 (7) ◽  
Author(s):  
Jing Zhang ◽  
Li Jing ◽  
Subee Tan ◽  
Er-Ming Zeng ◽  
Yingbo Lin ◽  
...  
Keyword(s):  
Glioblastoma Multiforme ◽  
High Throughput Screening ◽  
Synthetic Lethality ◽  
Gene Mutations ◽  
Primary Brain Tumor ◽  
Dna Double Strand Breaks ◽  
Synthetic Lethal ◽  
Oncogenic Mutation ◽  
Damage Repair ◽  
Genome Wide

Abstract Glioblastoma multiforme (GBM) is the most malignant primary brain tumor and has the highest mortality rate among cancers and high resistance to radiation and cytotoxic chemotherapy. Although some targeted therapies can partially inhibit oncogenic mutation-driven proliferation of GBM cells, therapies harnessing synthetic lethality are ‘coincidental’ treatments with high effectiveness in cancers with gene mutations, such as GBM, which frequently exhibits DNA-PKcs mutation. By implementing a highly efficient high-throughput screening (HTS) platform using an in-house-constructed genome-wide human microRNA inhibitor library, we demonstrated that miR-1193 inhibition sensitized GBM tumor cells with DNA-PKcs deficiency. Furthermore, we found that miR-1193 directly targets YY1AP1, leading to subsequent inhibition of FEN1, an important factor in DNA damage repair. Inhibition of miR-1193 resulted in accumulation of DNA double-strand breaks and thus increased genomic instability. RPA-coated ssDNA structures enhanced ATR checkpoint kinase activity, subsequently activating the CHK1/p53/apoptosis axis. These data provide a preclinical theory for the application of miR-1193 inhibition as a potential synthetic lethal approach targeting GBM cancer cells with DNA-PKcs deficiency.

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.

Sign in / Sign up

Export Citation Format

Share Document