title: EXD2 promotes homologous recombination by facilitating DNA end resection.
abstract: Repair of DNA double-strand breaks (DSBs) by homologous recombination (HR) is critical for survival and genome stability of individual cells and organisms, but also contributes to the genetic diversity of species. A vital step in HR is MRN-CtIP-dependent end resection, which generates the 3' single-stranded DNA overhangs required for the subsequent strand exchange reaction. Here, we identify EXD2 (also known as EXDL2) as an exonuclease essential for DSB resection and efficient HR. EXD2 is recruited to chromatin in a damage-dependent manner and confers resistance to DSB-inducing agents. EXD2 functionally interacts with the MRN complex to accelerate resection through its 3'-5' exonuclease activity, which efficiently processes double-stranded DNA substrates containing nicks. Finally, we establish that EXD2 stimulates both short- and long-range DSB resection, and thus, together with MRE11, is required for efficient HR. This establishes a key role for EXD2 in controlling the initial steps of chromosomal break repair.
authors.affiliation: Department of Oncology, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK.
authors.forename: Ronan
authors.initials: R
authors.lastname: Broderick
authors.affiliation: Department of Oncology, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK.
authors.forename: Jadwiga
authors.initials: J
authors.lastname: Nieminuszczy
authors.affiliation: Structural Genomics Consortium, Old Road Campus Research Building, Roosevelt Drive, University of Oxford, Oxford OX3 7DQ, UK.
authors.forename: Hannah T
authors.initials: HT
authors.lastname: Baddock
authors.affiliation: The Howard Hughes Medical Institute and Department of Molecular Biosciences, Institute for Cellular and Molecular Biology, University of Texas at Austin, Austin, TX 78712, USA.
authors.forename: Rajashree
authors.initials: R
authors.lastname: Deshpande
authors.affiliation: Structural Genomics Consortium, Old Road Campus Research Building, Roosevelt Drive, University of Oxford, Oxford OX3 7DQ, UK.
authors.forename: Opher
authors.initials: O
authors.lastname: Gileadi
authors.affiliation: The Howard Hughes Medical Institute and Department of Molecular Biosciences, Institute for Cellular and Molecular Biology, University of Texas at Austin, Austin, TX 78712, USA.
authors.forename: Tanya T
authors.initials: TT
authors.lastname: Paull
authors.affiliation: Department of Oncology, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: McHugh
authors.affiliation: Department of Oncology, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK.
authors.forename: Wojciech
authors.initials: W
authors.lastname: Niedzwiedz
mesh_terms: D002352:Carrier Proteins / Q000378:metabolism*; D002843:Chromatin / Q000378:metabolism; D004247:DNA / Q000378:metabolism*; D053903:DNA Breaks, Double-Stranded; D004260:DNA Repair / Q000235:genetics*; D059765:Homologous Recombination / Q000502:physiology; D006801:Humans; D009687:Nuclear Proteins / Q000378:metabolism; D016196:S Phase / Q000235:genetics
chemical_list: D002352:Carrier Proteins; D002843:Chromatin; D009687:Nuclear Proteins; D004247:DNA