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      Direct Involvement of Retinoblastoma Family Proteins in DNA Repair by Non-homologous End-Joining

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          Summary

          Deficiencies in DNA double-strand break (DSB) repair lead to genetic instability, a recognized cause of cancer initiation and evolution. We report that the retinoblastoma tumor suppressor protein (RB1) is required for DNA DSB repair by canonical non-homologous end-joining (cNHEJ). Support of cNHEJ involves a mechanism independent of RB1’s cell-cycle function and depends on its amino terminal domain with which it binds to NHEJ components XRCC5 and XRCC6. Cells with engineered loss of RB family function as well as cancer-derived cells with mutational RB1 loss show substantially reduced levels of cNHEJ. RB1 variants disabled for the interaction with XRCC5 and XRCC6, including a cancer-associated variant, are unable to support cNHEJ despite being able to confer cell-cycle control. Our data identify RB1 loss as a candidate driver of structural genomic instability and a causative factor for cancer somatic heterogeneity and evolution.

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          Highlights

          • RB1 associates with XRCC5 and XRCC6, involved in DNA repair by cNHEJ

          • RB family loss reduces cNHEJ and boosts repair-associated chromosomal aberrations

          • cNHEJ requires RB1’s N-terminal domain but is unrelated to cell-cycle control by RB1

          • RB1’s ability to support cNHEJ is targeted by mutation in cancer

          Abstract

          Loss of retinoblastoma protein (RB1) is common in various difficult-to-treat cancers. Cook et al. show that RB1 loss significantly impairs repair of DNA via non-homologous end-joining (NHEJ) and, in doing so, promotes genomic instability. These unexpected findings present opportunities for future cancer therapies that exploit this repair defect.

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          Most cited references72

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          The CRAPome: a Contaminant Repository for Affinity Purification Mass Spectrometry Data

          Affinity purification coupled with mass spectrometry (AP-MS) is now a widely used approach for the identification of protein-protein interactions. However, for any given protein of interest, determining which of the identified polypeptides represent bona fide interactors versus those that are background contaminants (e.g. proteins that interact with the solid-phase support, affinity reagent or epitope tag) is a challenging task. While the standard approach is to identify nonspecific interactions using one or more negative controls, most small-scale AP-MS studies do not capture a complete, accurate background protein set. Fortunately, negative controls are largely bait-independent. Hence, aggregating negative controls from multiple AP-MS studies can increase coverage and improve the characterization of background associated with a given experimental protocol. Here we present the Contaminant Repository for Affinity Purification (the CRAPome) and describe the use of this resource to score protein-protein interactions. The repository (currently available for Homo sapiens and Saccharomyces cerevisiae) and computational tools are freely available online at www.crapome.org.
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            DAVID: Database for Annotation, Visualization, and Integrated Discovery

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              Regulation of DNA repair throughout the cell cycle.

              The repair of DNA lesions that occur endogenously or in response to diverse genotoxic stresses is indispensable for genome integrity. DNA lesions activate checkpoint pathways that regulate specific DNA-repair mechanisms in the different phases of the cell cycle. Checkpoint-arrested cells resume cell-cycle progression once damage has been repaired, whereas cells with unrepairable DNA lesions undergo permanent cell-cycle arrest or apoptosis. Recent studies have provided insights into the mechanisms that contribute to DNA repair in specific cell-cycle phases and have highlighted the mechanisms that ensure cell-cycle progression or arrest in normal and cancerous cells.
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                Author and article information

                Contributors
                Journal
                Cell Rep
                Cell Rep
                Cell Reports
                Cell Press
                2211-1247
                31 March 2015
                31 March 2015
                : 10
                : 12
                : 2006-2018
                Affiliations
                [1 ]Division of Cancer Biology, Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK
                [2 ]Cancer Cell Signalling, UCL Cancer Institute, University College London, 72 Huntley Street, London WC1E 6DD, UK
                [3 ]Cancer Research UK Drug-DNA Interactions Research Group, UCL Cancer Institute, University College London, 72 Huntley Street, London WC1E 6DD, UK
                [4 ]Public Health England, Centre for Radiation, Chemical and Environmental Hazards, Chilton, Didcot OX11 0RQ, UK
                Author notes
                []Corresponding author paul.huang@ 123456icr.ac.uk
                [∗∗ ]Corresponding author s.mittnacht@ 123456ucl.ac.uk
                Article
                S2211-1247(15)00236-3
                10.1016/j.celrep.2015.02.059
                4386026
                25818292
                2f9ddb18-f4a9-45c4-b661-67575e7f2149
                © 2015 The Authors

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/).

                History
                : 21 June 2014
                : 2 January 2015
                : 24 February 2015
                Categories
                Article

                Cell biology
                Cell biology

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