Abstract PR01: A functional variomic chemi-genetic screen in C. elegans identifies new synthetic lethal interactions with PARP inhibition that are conserved from worm to human

2017 ◽  
Author(s):  
Nigel J. O'Neil ◽  
Melanie L. Bailey ◽  
Philip Hieter
Keyword(s):  
Genetic Screen ◽  
Parp Inhibition ◽  
Synthetic Lethal ◽  
C Elegans ◽  
Synthetic Lethal Interactions

scholarly journals Synthetic Lethal Interactions between EGFR and PARP Inhibition in Human Triple Negative Breast Cancer Cells

PLoS ONE ◽  
2012 ◽  
Vol 7 (10) ◽  
pp. e46614 ◽  
Author(s):  
Somaira Nowsheen ◽  
Tiffiny Cooper ◽  
Jennifer A. Stanley ◽  
Eddy S. Yang
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Triple Negative Breast Cancer ◽  
Breast Cancer Cells ◽  
Triple Negative ◽  
Parp Inhibition ◽  
Synthetic Lethal ◽  
Synthetic Lethal Interactions

scholarly journals Insights into the Involvement of Spliceosomal Mutations in Myelodysplastic Disorders from Analysis of SACY-1/DDX41 in Caenorhabditis elegans

Genetics ◽  
2020 ◽  
Vol 214 (4) ◽  
pp. 869-893 ◽  
Author(s):  
Tatsuya Tsukamoto ◽  
Micah D. Gearhart ◽  
Seongseop Kim ◽  
Gemechu Mekonnen ◽  
Caroline A. Spike ◽  
...  
Keyword(s):  
Caenorhabditis Elegans ◽  
Myelodysplastic Syndromes ◽  
Missense Mutations ◽  
Synthetic Lethal ◽  
C Elegans ◽  
Link Type ◽  
Dead Box ◽  
Synthetic Lethal Interactions ◽  
Biochemical Analyses ◽  
Cellular Phenotypes

Mutations affecting spliceosomal proteins are frequently found in hematological malignancies, including myelodysplastic syndromes and acute myeloid leukemia (AML). DDX41/Abstrakt is a metazoan-specific spliceosomal DEAD-box RNA helicase that is recurrently mutated in inherited myelodysplastic syndromes and in relapsing cases of AML. The genetic properties and genomic impacts of disease-causing missense mutations in DDX41 and other spliceosomal proteins have been uncertain. Here, we conduct a comprehensive analysis of the Caenorhabditis elegans DDX41 ortholog, SACY-1. Biochemical analyses defined SACY-1 as a component of the C. elegans spliceosome, and genetic analyses revealed synthetic lethal interactions with spliceosomal components. We used the auxin-inducible degradation system to analyze the consequence of SACY-1 depletion on the transcriptome using RNA sequencing. SACY-1 depletion impacts the transcriptome through splicing-dependent and splicing-independent mechanisms. Altered 3′ splice site usage represents the predominant splicing defect observed upon SACY-1 depletion, consistent with a role for SACY-1 in the second step of splicing. Missplicing events appear more prevalent in the soma than the germline, suggesting that surveillance mechanisms protect the germline from aberrant splicing. The transcriptome changes observed after SACY-1 depletion suggest that disruption of the spliceosome induces a stress response, which could contribute to the cellular phenotypes conferred by sacy-1 mutant alleles. Multiple sacy-1/ddx41 missense mutations, including the R525H human oncogenic variant, confer antimorphic activity, suggesting that their incorporation into the spliceosome is detrimental. Antagonistic variants that perturb the function of the spliceosome may be relevant to the disease-causing mutations, including DDX41, affecting highly conserved components of the spliceosome in humans.

scholarly journals Exploiting interconnected synthetic lethal interactions between PARP inhibition and cancer cell reversible senescence

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Hubert Fleury ◽  
Nicolas Malaquin ◽  
Véronique Tu ◽  
Sophie Gilbert ◽  
Aurélie Martinez ◽  
...  
Keyword(s):  
Cancer Cell ◽  
Parp Inhibition ◽  
Synthetic Lethal ◽  
Synthetic Lethal Interactions

scholarly journals Genome-wide RNAi screen for synthetic lethal interactions with the C. elegans kinesin-5 homolog BMK-1

2015 ◽  
Vol 2 (1) ◽  
Author(s):  
André F. Maia ◽  
Marvin E. Tanenbaum ◽  
Matilde Galli ◽  
Daphne Lelieveld ◽  
David A. Egan ◽  
...  
Keyword(s):  
Rnai Screen ◽  
Synthetic Lethal ◽  
C Elegans ◽  
Genome Wide ◽  
Synthetic Lethal Interactions

Synthetic Lethal Interactions in Cancer Therapy

2017 ◽  
Vol 17 (4) ◽  
pp. 304-310 ◽  
Author(s):  
Xinwei Geng ◽  
Xiaohui Wang ◽  
Dan Zhu ◽  
Songmin Ying
Keyword(s):  
Cancer Therapy ◽  
Synthetic Lethal ◽  
Synthetic Lethal Interactions

scholarly journals Combinatorial CRISPR screen identifies fitness effects of gene paralogues

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Nicola A. Thompson ◽  
Marco Ranzani ◽  
Louise van der Weyden ◽  
Vivek Iyer ◽  
Victoria Offord ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Cell Lines ◽  
Unknown Function ◽  
Single Copy ◽  
Genetic Redundancy ◽  
Synthetic Lethal ◽  
Fitness Effects ◽  
Synthetic Lethal Interactions ◽  
Crispr Screen ◽  
Multiple Cell

AbstractGenetic redundancy has evolved as a way for human cells to survive the loss of genes that are single copy and essential in other organisms, but also allows tumours to survive despite having highly rearranged genomes. In this study we CRISPR screen 1191 gene pairs, including paralogues and known and predicted synthetic lethal interactions to identify 105 gene combinations whose co-disruption results in a loss of cellular fitness. 27 pairs influence fitness across multiple cell lines including the paralogues FAM50A/FAM50B, two genes of unknown function. Silencing of FAM50B occurs across a range of tumour types and in this context disruption of FAM50A reduces cellular fitness whilst promoting micronucleus formation and extensive perturbation of transcriptional programmes. Our studies reveal the fitness effects of FAM50A/FAM50B in cancer cells.

Abstract B09: Combining proteomics and genetic screens to identify KRAS synthetic lethal interactions

2020 ◽  
Author(s):  
Shikha S. Sheth ◽  
Danielle R. Cook ◽  
Samantha D. Strasser ◽  
Timothy D. Martin ◽  
Sneha Menon ◽  
...  
Keyword(s):  
Genetic Screens ◽  
Synthetic Lethal ◽  
Synthetic Lethal Interactions
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