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A Role for the Malignant Brain Tumour (MBT) Domain Protein LIN-61 in DNA Double-Strand Break Repair by Homologous Recombination

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      Abstract

      Malignant brain tumour (MBT) domain proteins are transcriptional repressors that function within Polycomb complexes. Some MBT genes are tumour suppressors, but how they prevent tumourigenesis is unknown. The Caenorhabditis elegans MBT protein LIN-61 is a member of the synMuvB chromatin-remodelling proteins that control vulval development. Here we report a new role for LIN-61: it protects the genome by promoting homologous recombination (HR) for the repair of DNA double-strand breaks (DSBs). lin-61 mutants manifest numerous problems associated with defective HR in germ and somatic cells but remain proficient in meiotic recombination. They are hypersensitive to ionizing radiation and interstrand crosslinks but not UV light. Using a novel reporter system that monitors repair of a defined DSB in C. elegans somatic cells, we show that LIN-61 contributes to HR. The involvement of this MBT protein in HR raises the possibility that MBT–deficient tumours may also have defective DSB repair.

      Author Summary

      The genome is continually under threat from exogenous sources of DNA damage, as well as from sources that originate within the cell. DNA double-strand breaks (DSBs) are arguably the most problematic type of damage as they can cause dangerous chromosome rearrangements, which can lead to cancer, as well as mutation at the break site and/or cell death. A complex network of molecular pathways, collectively referred to as the DNA damage response (DDR), have evolved to protect the cell from these threats. We have discovered a new DDR factor, LIN-61, that promotes the repair of DSBs. This is a novel and unexpected role for LIN-61, which was previously known to act as a regulator of gene transcription during development.

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      Most cited references 62

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            Author and article information

            Affiliations
            Department of Toxicogenetics, Leiden University Medical Center, Leiden, The Netherlands
            University of Washington, United States of America
            Author notes

            The authors have declared that no competing interests exist.

            Conceived and designed the experiments: NMJ MT. Performed the experiments: NMJ BBLGL. Analyzed the data: NMJ BBLGL MT. Wrote the paper: NMJ MT.

            Contributors
            Role: Editor
            Journal
            PLoS Genet
            PLoS Genet
            plos
            plosgen
            PLoS Genetics
            Public Library of Science (San Francisco, USA )
            1553-7390
            1553-7404
            March 2013
            March 2013
            7 March 2013
            : 9
            : 3
            23505385 3591299 PGENETICS-D-12-01003 10.1371/journal.pgen.1003339

            This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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            Pages: 14
            Funding
            This work was funded by European Research Council Starting Grant (203379, “DSBrepair”) and by Dutch Cancer Society (KWF) grant KWF-2008-4107. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
            Categories
            Research Article
            Biology
            Model Organisms
            Animal Models
            Caenorhabditis Elegans
            Molecular Cell Biology
            Nucleic Acids
            DNA
            DNA repair

            Genetics

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