Synthetic Lethality of Cohesins with PARPs and Replication Fork Mediators
Publication Date
March 08, 2012
Journal
PLOS Genetics
Authors
Jessica L. Mc Lellan, Nigel J. O'neil, Irene Barrett, Elizabeth Ferree, et al
Volume
8
Issue
3
Pages
e1002574
DOI
https://dx.plos.org/10.1371/journal.pgen.1002574
Publisher URL
http://journals.plos.org/plosgenetics/article?id=10.1371%2Fjournal.pgen.1002574
PubMed
http://www.ncbi.nlm.nih.gov/pubmed/22412391
PubMed Central
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3297586
Europe PMC
http://europepmc.org/abstract/MED/22412391
Web of Science
000302254800049
Scopus
84859223202
Mendeley
http://www.mendeley.com/research/synthetic-lethality-cohesins-parps-replication-fork-mediators
Events
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Mendeley | Further Information

{"title"=>"Synthetic lethality of cohesins with PARPs and replication fork mediators", "type"=>"journal", "authors"=>[{"first_name"=>"Jessica L.", "last_name"=>"McLellan", "scopus_author_id"=>"35754764800"}, {"first_name"=>"Nigel J.", "last_name"=>"O'Neil", "scopus_author_id"=>"6602913979"}, {"first_name"=>"Irene", "last_name"=>"Barrett", "scopus_author_id"=>"57198130256"}, {"first_name"=>"Elizabeth", "last_name"=>"Ferree", "scopus_author_id"=>"55165418500"}, {"first_name"=>"Derek M.", "last_name"=>"van Pel", "scopus_author_id"=>"55163809500"}, {"first_name"=>"Kevin", "last_name"=>"Ushey", "scopus_author_id"=>"55164763300"}, {"first_name"=>"Payal", "last_name"=>"Sipahimalani", "scopus_author_id"=>"16647178800"}, {"first_name"=>"Jennifer", "last_name"=>"Bryan", "scopus_author_id"=>"8686952900"}, {"first_name"=>"Ann M.", "last_name"=>"Rose", "scopus_author_id"=>"7201499653"}, {"first_name"=>"Philip", "last_name"=>"Hieter", "scopus_author_id"=>"7006930573"}], "year"=>2012, "source"=>"PLoS Genetics", "identifiers"=>{"pui"=>"364556484", "issn"=>"15537390", "isbn"=>"1553-7404 (Electronic)\\r1553-7390 (Linking)", "doi"=>"10.1371/journal.pgen.1002574", "scopus"=>"2-s2.0-84859223202", "pmid"=>"22412391", "sgr"=>"84859223202"}, "id"=>"4c362f35-cca6-3c0c-96d6-65f1f4bfb495", "abstract"=>"Synthetic lethality has been proposed as a way to leverage the genetic differences found in tumor cells to affect their selective killing. Cohesins, which tether sister chromatids together until anaphase onset, are mutated in a variety of tumor types. The elucidation of synthetic lethal interactions with cohesin mutants therefore identifies potential therapeutic targets. We used a cross-species approach to identify robust negative genetic interactions with cohesin mutants. Utilizing essential and non-essential mutant synthetic genetic arrays in Saccharomyces cerevisiae, we screened genome-wide for genetic interactions with hypomorphic mutations in cohesin genes. A somatic cell proliferation assay in Caenorhabditis elegans demonstrated that the majority of interactions were conserved. Analysis of the interactions found that cohesin mutants require the function of genes that mediate replication fork progression. Conservation of these interactions between replication fork mediators and cohesin in both yeast and C. elegans prompted us to test whether other replication fork mediators not found in the yeast were required for viability in cohesin mutants. PARP1 has roles in the DNA damage response but also in the restart of stalled replication forks. We found that a hypomorphic allele of the C. elegans SMC1 orthologue, him-1(e879), genetically interacted with mutations in the orthologues of PAR metabolism genes resulting in a reduced brood size and somatic cell defects. We then demonstrated that this interaction is conserved in human cells by showing that PARP inhibitors reduce the viability of cultured human cells depleted for cohesin components. This work demonstrates that large-scale genetic interaction screening in yeast can identify clinically relevant genetic interactions and suggests that PARP inhibitors, which are currently undergoing clinical trials as a treatment of homologous recombination-deficient cancers, may be effective in treating cancers that harbor cohesin mutations.", "link"=>"http://www.mendeley.com/research/synthetic-lethality-cohesins-parps-replication-fork-mediators", "reader_count"=>72, "reader_count_by_academic_status"=>{"Professor > Associate Professor"=>11, "Researcher"=>24, "Student > Doctoral Student"=>2, "Student > Ph. D. Student"=>22, "Student > Postgraduate"=>2, "Other"=>3, "Student > Master"=>1, "Student > Bachelor"=>5, "Lecturer"=>1, "Professor"=>1}, "reader_count_by_user_role"=>{"Professor > Associate Professor"=>11, "Researcher"=>24, "Student > Doctoral Student"=>2, "Student > Ph. D. Student"=>22, "Student > Postgraduate"=>2, "Other"=>3, "Student > Master"=>1, "Student > Bachelor"=>5, "Lecturer"=>1, "Professor"=>1}, "reader_count_by_subject_area"=>{"Environmental Science"=>1, "Biochemistry, Genetics and Molecular Biology"=>14, "Agricultural and Biological Sciences"=>47, "Medicine and Dentistry"=>6, "Pharmacology, Toxicology and Pharmaceutical Science"=>1, "Chemistry"=>1, "Computer Science"=>2}, "reader_count_by_subdiscipline"=>{"Medicine and Dentistry"=>{"Medicine and Dentistry"=>6}, "Chemistry"=>{"Chemistry"=>1}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>47}, "Computer Science"=>{"Computer Science"=>2}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>14}, "Environmental Science"=>{"Environmental Science"=>1}, "Pharmacology, Toxicology and Pharmaceutical Science"=>{"Pharmacology, Toxicology and Pharmaceutical Science"=>1}}, "reader_count_by_country"=>{"Canada"=>1, "United States"=>1, "Japan"=>1, "United Kingdom"=>1, "France"=>1, "Germany"=>1}, "group_count"=>0}

Scopus | Further Information

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/670012"], "description"=>"<p>Graph depicting the frequency of worms with a protruding vulva (Pvl) when <i>VC2010</i> (WT) and <i>SMC1/him-1(e879)</i> strains are treated with various RNAi constructs. The RNAis tested targeted the <i>C. elegans</i> homologs of genes that interact with one of the cohesin query genes in the <i>S. cerevisiae</i> validated network (<a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1002574#pgen-1002574-g001\" target=\"_blank\">Figure 1C</a>). Homologs with associated e-value BLAST scores can be found in <a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1002574#pgen.1002574.s011\" target=\"_blank\">Table S1</a>. Interactions are ranked by the difference between the frequency of Pvl in VC2010 and <i>him-1</i> strains. The predicted value is the sum of both the him-1 and N2 background Pvl frequencies and the effect of the RNAi on WT. <i>unc-22</i> and 6 randomly chosen RNAi clones from chromosome 1 are included as negative controls. Error bars represent SEM.</p>", "links"=>[], "tags"=>["genetics and genomics", "microbiology"], "article_id"=>340499, "categories"=>["Genetics", "Microbiology"], "users"=>["Jessica L. McLellan", "Nigel J. O'Neil", "Irene Barrett", "Elizabeth Ferree", "Derek M. van Pel", "Kevin Ushey", "Payal Sipahimalani", "Jennifer Bryan", "Ann M. Rose", "Philip Hieter"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1002574.g002", "stats"=>{"downloads"=>1, "page_views"=>10, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_C_elegans_genetic_interactions_/340499", "title"=>"<i>C. elegans</i> genetic interactions.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-03-08 00:08:19"}
  • {"files"=>["https://ndownloader.figshare.com/files/670125"], "description"=>"<p>A) The validated <i>S. cerevisiae</i> cohesion network was filtered to include only SL interactions. Gene nodes are colored according to the legend in <a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1002574#pgen-1002574-g001\" target=\"_blank\">Figure 1C</a>. B) Brood size (total number of eggs laid), embryonic lethality, and percentage of male progeny and C) Frequency of Pvl in the indicated single and double mutants. Error bars represent SEM.</p>", "links"=>[], "tags"=>["cohesin", "requires", "replication"], "article_id"=>340606, "categories"=>["Genetics", "Microbiology"], "users"=>["Jessica L. McLellan", "Nigel J. O'Neil", "Irene Barrett", "Elizabeth Ferree", "Derek M. van Pel", "Kevin Ushey", "Payal Sipahimalani", "Jennifer Bryan", "Ann M. Rose", "Philip Hieter"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1002574.g003", "stats"=>{"downloads"=>1, "page_views"=>3, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Sub_optimal_cohesin_requires_replication_fork_mediators_/340606", "title"=>"Sub-optimal cohesin requires replication fork mediators.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-03-08 00:10:06"}
  • {"files"=>["https://ndownloader.figshare.com/files/670319"], "description"=>"<p>All experiments were performed with HTB-38, a near triploid colon cancer derived cell line that is MMR proficient. A) Western blot stained with anti-PAR. BV80 is MLH1−/− and is the matched line to BV79 which is MLH1+/−. RPE-1 was used as a control cell line for measuring PAR levels. RPE-1 is an hTERT immortalized retina epithelial cell line. B) Normalized colony numbers for HTB-38 cells treated with the indicated siRNA and exposed to 0.6 µM olaparib. C) Raw colony numbers for the clonagenic assay shown in B. Error bars represent SEM.</p>", "links"=>[], "tags"=>["genetically", "htb-38"], "article_id"=>340798, "categories"=>["Genetics", "Microbiology"], "users"=>["Jessica L. McLellan", "Nigel J. O'Neil", "Irene Barrett", "Elizabeth Ferree", "Derek M. van Pel", "Kevin Ushey", "Payal Sipahimalani", "Jennifer Bryan", "Ann M. Rose", "Philip Hieter"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1002574.g005", "stats"=>{"downloads"=>1, "page_views"=>2, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_SMC1_and_PARP_genetically_interact_in_HTB_38_human_cells_/340798", "title"=>"<i>SMC1</i> and <i>PARP</i> genetically interact in HTB-38 human cells.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-03-08 00:13:18"}
  • {"files"=>["https://ndownloader.figshare.com/files/670455"], "description"=>"*<p>Silent mutations not reported in this table. Amino acid: aa.</p>", "links"=>[], "tags"=>["cohesin", "genes", "seen"], "article_id"=>340937, "categories"=>["Genetics", "Microbiology"], "users"=>["Jessica L. McLellan", "Nigel J. O'Neil", "Irene Barrett", "Elizabeth Ferree", "Derek M. van Pel", "Kevin Ushey", "Payal Sipahimalani", "Jennifer Bryan", "Ann M. Rose", "Philip Hieter"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1002574.t001", "stats"=>{"downloads"=>0, "page_views"=>1, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Mutations_in_cohesin_genes_seen_in_tumors_/340937", "title"=>"Mutations in cohesin genes seen in tumors.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2012-03-08 00:15:37"}
  • {"files"=>["https://ndownloader.figshare.com/files/669931"], "description"=>"<p>A) Venn diagrams depicting how SGA data was filtered. i. Interactions that had a negative interaction value and were statistically significant (p-value<0.05). ii. Interactions that had a relatively weak interaction score (Experimental value – Control value>−.3) were eliminated to enrich for biologically significant interactions. iii. Genes were eliminated if they failed to interact with ≥2 of the cohesin query genes and if they did not have a human homolog (<a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1002574#pgen.1002574.s013\" target=\"_blank\">Table S3</a>). iv. Summary of the final network after random spore and growth curve retesting and validation. The total number of interactions in a given Venn diagram is underlined. The total number of genes is shown in red. The numbers in brackets indicate interacting genes remaining after removal of 6 genes for technical reasons. B) Representative subset of growth curve data. The T-stat, which takes into account the interaction magnitude and statistical significance, is shown in blue. All growth curve data can be found in <a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1002574#pgen.1002574.s003\" target=\"_blank\">Figures S3</a>, <a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1002574#pgen.1002574.s004\" target=\"_blank\">S4</a>, <a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1002574#pgen.1002574.s005\" target=\"_blank\">S5</a>, <a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1002574#pgen.1002574.s006\" target=\"_blank\">S6</a> and <a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1002574#pgen.1002574.s011\" target=\"_blank\">Tables S1</a>, <a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1002574#pgen.1002574.s012\" target=\"_blank\">S2</a>, <a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1002574#pgen.1002574.s013\" target=\"_blank\">S3</a>. C) Expanded view of the final network summarized in A iv. Red lines indicate SL interactions and black lines represent SS interactions. The black line thickness represents interaction strength.</p>", "links"=>[], "tags"=>["cohesin"], "article_id"=>340410, "categories"=>["Genetics", "Microbiology"], "users"=>["Jessica L. McLellan", "Nigel J. O'Neil", "Irene Barrett", "Elizabeth Ferree", "Derek M. van Pel", "Kevin Ushey", "Payal Sipahimalani", "Jennifer Bryan", "Ann M. Rose", "Philip Hieter"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1002574.g001", "stats"=>{"downloads"=>1, "page_views"=>4, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_S_cerevisiae_cohesin_genetic_interaction_network_/340410", "title"=>"<i>S. cerevisiae</i> cohesin genetic interaction network.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-03-08 00:06:50"}
  • {"files"=>["https://ndownloader.figshare.com/files/345234", "https://ndownloader.figshare.com/files/345299", "https://ndownloader.figshare.com/files/345373", "https://ndownloader.figshare.com/files/345447", "https://ndownloader.figshare.com/files/345517", "https://ndownloader.figshare.com/files/345575", "https://ndownloader.figshare.com/files/345688", "https://ndownloader.figshare.com/files/345744", "https://ndownloader.figshare.com/files/345786", "https://ndownloader.figshare.com/files/345856", "https://ndownloader.figshare.com/files/345923", "https://ndownloader.figshare.com/files/346022", "https://ndownloader.figshare.com/files/346086", "https://ndownloader.figshare.com/files/346180", "https://ndownloader.figshare.com/files/346255", "https://ndownloader.figshare.com/files/346308", "https://ndownloader.figshare.com/files/346370", "https://ndownloader.figshare.com/files/346435", "https://ndownloader.figshare.com/files/346506", "https://ndownloader.figshare.com/files/346552"], "description"=>"<div><p>Synthetic lethality has been proposed as a way to leverage the genetic differences found in tumor cells to affect their selective killing. Cohesins, which tether sister chromatids together until anaphase onset, are mutated in a variety of tumor types. The elucidation of synthetic lethal interactions with cohesin mutants therefore identifies potential therapeutic targets. We used a cross-species approach to identify robust negative genetic interactions with cohesin mutants. Utilizing essential and non-essential mutant synthetic genetic arrays in <em>Saccharomyces cerevisiae</em>, we screened genome-wide for genetic interactions with hypomorphic mutations in cohesin genes. A somatic cell proliferation assay in <em>Caenorhabditis elegans</em> demonstrated that the majority of interactions were conserved. Analysis of the interactions found that cohesin mutants require the function of genes that mediate replication fork progression. Conservation of these interactions between replication fork mediators and cohesin in both yeast and <em>C. elegans</em> prompted us to test whether other replication fork mediators not found in the yeast were required for viability in cohesin mutants. PARP1 has roles in the DNA damage response but also in the restart of stalled replication forks. We found that a hypomorphic allele of the <em>C. elegans SMC1</em> orthologue, <em>him-1(e879)</em>, genetically interacted with mutations in the orthologues of <em>PAR</em> metabolism genes resulting in a reduced brood size and somatic cell defects. We then demonstrated that this interaction is conserved in human cells by showing that PARP inhibitors reduce the viability of cultured human cells depleted for cohesin components. This work demonstrates that large-scale genetic interaction screening in yeast can identify clinically relevant genetic interactions and suggests that PARP inhibitors, which are currently undergoing clinical trials as a treatment of homologous recombination-deficient cancers, may be effective in treating cancers that harbor cohesin mutations.</p> </div>", "links"=>[], "tags"=>["synthetic", "lethality", "cohesins", "parps", "replication", "mediators"], "article_id"=>128252, "categories"=>["Genetics", "Microbiology"], "users"=>["Jessica L. McLellan", "Nigel J. O'Neil", "Irene Barrett", "Elizabeth Ferree", "Derek M. van Pel", "Kevin Ushey", "Payal Sipahimalani", "Jennifer Bryan", "Ann M. Rose", "Philip Hieter"], "doi"=>["https://dx.doi.org/10.1371/journal.pgen.1002574.s001", "https://dx.doi.org/10.1371/journal.pgen.1002574.s002", "https://dx.doi.org/10.1371/journal.pgen.1002574.s003", "https://dx.doi.org/10.1371/journal.pgen.1002574.s004", "https://dx.doi.org/10.1371/journal.pgen.1002574.s005", "https://dx.doi.org/10.1371/journal.pgen.1002574.s006", "https://dx.doi.org/10.1371/journal.pgen.1002574.s007", "https://dx.doi.org/10.1371/journal.pgen.1002574.s008", "https://dx.doi.org/10.1371/journal.pgen.1002574.s009", "https://dx.doi.org/10.1371/journal.pgen.1002574.s010", "https://dx.doi.org/10.1371/journal.pgen.1002574.s011", "https://dx.doi.org/10.1371/journal.pgen.1002574.s012", "https://dx.doi.org/10.1371/journal.pgen.1002574.s013", "https://dx.doi.org/10.1371/journal.pgen.1002574.s014", "https://dx.doi.org/10.1371/journal.pgen.1002574.s015", "https://dx.doi.org/10.1371/journal.pgen.1002574.s016", "https://dx.doi.org/10.1371/journal.pgen.1002574.s017", "https://dx.doi.org/10.1371/journal.pgen.1002574.s018", "https://dx.doi.org/10.1371/journal.pgen.1002574.s019", "https://dx.doi.org/10.1371/journal.pgen.1002574.s020"], "stats"=>{"downloads"=>80, "page_views"=>38, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/Synthetic_Lethality_of_Cohesins_with_PARPs_and_Replication_Fork_Mediators/128252", "title"=>"Synthetic Lethality of Cohesins with PARPs and Replication Fork Mediators", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2012-03-08 02:17:32"}
  • {"files"=>["https://ndownloader.figshare.com/files/670207"], "description"=>"<p>All experiments were performed with HCT116, a near diploid, colon cancer derived cell line that is MMR deficient. In all panels HCT116 cells are treated with siRNA targeting <i>GAPDH</i>, <i>BRCA1</i> or <i>SMC1</i> or untreated (in indicated). A) 24 well plate clonagenic survival assay with HCT116 siRNA treated cells exposed to olaparib concentrations up to 1.5 µM. B) 10 cm dish clonagenic survival assay looking at the number of colonies after 10 days in the presence of 0.6 µM olaparib. C) Normalized colony numbers from the clonagenic assay. D) HC-DIM counting Hoescht positive nuclei of siRNA treated cells after 3 days of olaparib exposure. E) Western blot of samples collected from the 10 cm survival assay (B). Error bars represent SEM.</p>", "links"=>[], "tags"=>["sirna", "treated", "cells", "parp", "inhibitor"], "article_id"=>340686, "categories"=>["Genetics", "Microbiology"], "users"=>["Jessica L. McLellan", "Nigel J. O'Neil", "Irene Barrett", "Elizabeth Ferree", "Derek M. van Pel", "Kevin Ushey", "Payal Sipahimalani", "Jennifer Bryan", "Ann M. Rose", "Philip Hieter"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1002574.g004", "stats"=>{"downloads"=>1, "page_views"=>23, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_SMC1_siRNA_treated_human_cells_are_sensitive_to_the_PARP_inhibitor_olaparib_/340686", "title"=>"<i>SMC1</i> siRNA treated human cells are sensitive to the PARP inhibitor olaparib.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-03-08 00:11:26"}

PMC Usage Stats | Further Information

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