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      Mapping of DDX11 genetic interactions defines sister chromatid cohesion as the major dependency

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          Abstract

          DDX11/Chl1R is a conserved DNA helicase with roles in genome maintenance, DNA replication, and chromatid cohesion. Loss of DDX11 in humans leads to the rare cohesinopathy Warsaw breakage syndrome. DDX11 has also been implicated in human cancer where it has been proposed to have an oncogenic role and possibly to constitute a therapeutic target. Given the multiple roles of DDX11 in genome stability and its potential as an anticancer target, we set out to define a complete genetic interaction profile of DDX11 loss in human cell lines. Screening the human genome with clustered regularly interspaced short palindromic repeats (CRISPR) guide RNA drop out screens in DDX11-wildtype (WT) or DDX11-deficient cells revealed a strong enrichment of genes with functions related to sister chromatid cohesion. We confirm synthetic lethal relationships between DDX11 and the tumor suppressor cohesin subunit STAG2, which is frequently mutated in several cancer types and the kinase HASPIN. This screen highlights the importance of cohesion in cells lacking DDX11 and suggests DDX11 may be a therapeutic target for tumors with mutations in STAG2.

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          Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy.

          BRCA1 and BRCA2 are important for DNA double-strand break repair by homologous recombination, and mutations in these genes predispose to breast and other cancers. Poly(ADP-ribose) polymerase (PARP) is an enzyme involved in base excision repair, a key pathway in the repair of DNA single-strand breaks. We show here that BRCA1 or BRCA2 dysfunction unexpectedly and profoundly sensitizes cells to the inhibition of PARP enzymatic activity, resulting in chromosomal instability, cell cycle arrest and subsequent apoptosis. This seems to be because the inhibition of PARP leads to the persistence of DNA lesions normally repaired by homologous recombination. These results illustrate how different pathways cooperate to repair damage, and suggest that the targeted inhibition of particular DNA repair pathways may allow the design of specific and less toxic therapies for cancer.
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            Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase.

            Poly(ADP-ribose) polymerase (PARP1) facilitates DNA repair by binding to DNA breaks and attracting DNA repair proteins to the site of damage. Nevertheless, PARP1-/- mice are viable, fertile and do not develop early onset tumours. Here, we show that PARP inhibitors trigger gamma-H2AX and RAD51 foci formation. We propose that, in the absence of PARP1, spontaneous single-strand breaks collapse replication forks and trigger homologous recombination for repair. Furthermore, we show that BRCA2-deficient cells, as a result of their deficiency in homologous recombination, are acutely sensitive to PARP inhibitors, presumably because resultant collapsed replication forks are no longer repaired. Thus, PARP1 activity is essential in homologous recombination-deficient BRCA2 mutant cells. We exploit this requirement in order to kill BRCA2-deficient tumours by PARP inhibition alone. Treatment with PARP inhibitors is likely to be highly tumour specific, because only the tumours (which are BRCA2-/-) in BRCA2+/- patients are defective in homologous recombination. The use of an inhibitor of a DNA repair enzyme alone to selectively kill a tumour, in the absence of an exogenous DNA-damaging agent, represents a new concept in cancer treatment.
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              PANTHER version 16: a revised family classification, tree-based classification tool, enhancer regions and extensive API

              Abstract PANTHER (Protein Analysis Through Evolutionary Relationships, http://www.pantherdb.org) is a resource for the evolutionary and functional classification of protein-coding genes from all domains of life. The evolutionary classification is based on a library of over 15,000 phylogenetic trees, and the functional classifications include Gene Ontology terms and pathways. Here, we analyze the current coverage of genes from genomes in different taxonomic groups, so that users can better understand what to expect when analyzing a gene list using PANTHER tools. We also describe extensive improvements to PANTHER made in the past two years. The PANTHER Protein Class ontology has been completely refactored, and 6101 PANTHER families have been manually assigned to a Protein Class, providing a high level classification of protein families and their genes. Users can access the TreeGrafter tool to add their own protein sequences to the reference phylogenetic trees in PANTHER, to infer evolutionary context as well as fine-grained annotations. We have added human enhancer-gene links that associate non-coding regions with the annotated human genes in PANTHER. We have also expanded the available services for programmatic access to PANTHER tools and data via application programming interfaces (APIs). Other improvements include additional plant genomes and an updated PANTHER GO-slim.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                G3 (Bethesda)
                Genetics
                g3journal
                G3: Genes|Genomes|Genetics
                Oxford University Press (US )
                2160-1836
                May 2024
                13 March 2024
                13 March 2024
                : 14
                : 5
                : jkae052
                Affiliations
                Michael Smith Laboratories, University of British Columbia , 2185 East Mall, Vancouver, British Columbia, V6T 1Z4, Canada
                Terry Fox Laboratory, BC Cancer Research Institute , 675 West 10th Avenue, Vancouver, British Columbia, V5Z 1L3, Canada
                Donnelly Centre, University of Toronto , Toronto, Ontario, M5S 3E1, Canada
                Donnelly Centre, University of Toronto , Toronto, Ontario, M5S 3E1, Canada
                Donnelly Centre, University of Toronto , Toronto, Ontario, M5S 3E1, Canada
                Michael Smith Laboratories, University of British Columbia , 2185 East Mall, Vancouver, British Columbia, V6T 1Z4, Canada
                Donnelly Centre, University of Toronto , Toronto, Ontario, M5S 3E1, Canada
                Department of Molecular Genetics, University of Toronto , Toronto, Ontario, M5S1A8, Canada
                Institute of Biomedical Engineering, University of Toronto , Toronto, Ontario, M5S3E1, Canada
                Terry Fox Laboratory, BC Cancer Research Institute , 675 West 10th Avenue, Vancouver, British Columbia, V5Z 1L3, Canada
                Michael Smith Laboratories, University of British Columbia , 2185 East Mall, Vancouver, British Columbia, V6T 1Z4, Canada
                Author notes
                Corresponding author: Michael Smith Laboratories, University of British Columbia, 2185 East Mall, British Columbia, Vancouver, V6T1Z4, Canada. Email: hieter@ 123456msl.ubc.ca
                Corresponding author: Terry Fox Laboratory, BC Cancer, 675 West 10 th Avenue, British Columbia, Vancouver, V5L1Z3, Canada. Email: pstirling@ 123456bccrc.ca

                Conflicts of interest The author(s) declare no conflicts of interest.

                Author information
                https://orcid.org/0000-0003-4446-8302
                https://orcid.org/0000-0002-1992-6976
                https://orcid.org/0000-0002-5663-8586
                Article
                jkae052
                10.1093/g3journal/jkae052
                11075568
                38478595
                40280f0c-755e-439a-a8c2-6b8842af04ca
                © The Author(s) 2024. Published by Oxford University Press on behalf of The Genetics Society of America.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 22 January 2024
                : 04 March 2024
                : 04 April 2024
                Page count
                Pages: 11
                Funding
                Funded by: Canadian Institutes of Health Research, DOI 10.13039/501100000024;
                Award ID: 398871
                Funded by: Canadian Cancer Society Research Institute, DOI 10.13039/501100000015;
                Award ID: 704252
                Funded by: Canadian Institute for Advanced Research Genetic Networks Catalyst;
                Categories
                Mutant Screen Report
                AcademicSubjects/SCI01180
                AcademicSubjects/SCI01140

                Genetics
                ddx11,helicase,synthetic lethality,cohesin,crispr
                Genetics
                ddx11, helicase, synthetic lethality, cohesin, crispr

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