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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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          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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              The prime objective for every life form is to deliver its genetic material, intact and unchanged, to the next generation. This must be achieved despite constant assaults by endogenous and environmental agents on the DNA. To counter this threat, life has evolved several systems to detect DNA damage, signal its presence and mediate its repair. Such responses, which have an impact on a wide range of cellular events, are biologically significant because they prevent diverse human diseases. Our improving understanding of DNA-damage responses is providing new avenues for disease management.

                Author and article information

                Role: Editor
                PLoS Genet
                PLoS Genet
                PLoS Genetics
                Public Library of Science (San Francisco, USA )
                March 2013
                March 2013
                7 March 2013
                : 9
                : 3
                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.


                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.

                Pages: 14
                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.
                Research Article
                Model Organisms
                Animal Models
                Caenorhabditis Elegans
                Molecular Cell Biology
                Nucleic Acids
                DNA repair



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