title: BOD1L Is Required to Suppress Deleterious Resection of Stressed Replication Forks.
abstract: Recognition and repair of damaged replication forks are essential to maintain genome stability and are coordinated by the combined action of the Fanconi anemia and homologous recombination pathways. These pathways are vital to protect stalled replication forks from uncontrolled nucleolytic activity, which otherwise causes irreparable genomic damage. Here, we identify BOD1L as a component of this fork protection pathway, which safeguards genome stability after replication stress. Loss of BOD1L confers exquisite cellular sensitivity to replication stress and uncontrolled resection of damaged replication forks, due to a failure to stabilize RAD51 at these forks. Blocking DNA2-dependent resection, or downregulation of the helicases BLM and FBH1, suppresses both catastrophic fork processing and the accumulation of chromosomal damage in BOD1L-deficient cells. Thus, our work implicates BOD1L as a critical regulator of genome integrity that restrains nucleolytic degradation of damaged replication forks.
authors.affiliation: School of Cancer Sciences, University of Birmingham, Birmingham B15 2TT, UK.
authors.forename: Martin R
authors.initials: MR
authors.lastname: Higgs
authors.affiliation: School of Cancer Sciences, University of Birmingham, Birmingham B15 2TT, UK.
authors.forename: John J
authors.initials: JJ
authors.lastname: Reynolds
authors.affiliation: The Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK.
authors.forename: Alicja
authors.initials: A
authors.lastname: Winczura
authors.affiliation: The Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK.
authors.forename: Andrew N
authors.initials: AN
authors.lastname: Blackford
authors.affiliation: The Francis Crick Institute, Clare Hall Laboratories, South Mimms, Herts EN6 3LD, UK.
authors.forename: Valérie
authors.initials: V
authors.lastname: Borel
authors.affiliation: School of Cancer Sciences, University of Birmingham, Birmingham B15 2TT, UK.
authors.forename: Edward S
authors.initials: ES
authors.lastname: Miller
authors.affiliation: School of Cancer Sciences, University of Birmingham, Birmingham B15 2TT, UK.
authors.forename: Anastasia
authors.initials: A
authors.lastname: Zlatanou
authors.affiliation: The Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK.
authors.forename: Jadwiga
authors.initials: J
authors.lastname: Nieminuszczy
authors.affiliation: School of Cancer Sciences, University of Birmingham, Birmingham B15 2TT, UK.
authors.forename: Ellis L
authors.initials: EL
authors.lastname: Ryan
authors.affiliation: School of Cancer Sciences, University of Birmingham, Birmingham B15 2TT, UK.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Davies
authors.affiliation: School of Cancer Sciences, University of Birmingham, Birmingham B15 2TT, UK.
authors.forename: Tatjana
authors.initials: T
authors.lastname: Stankovic
authors.affiliation: The Francis Crick Institute, Clare Hall Laboratories, South Mimms, Herts EN6 3LD, UK.
authors.forename: Simon J
authors.initials: SJ
authors.lastname: Boulton
authors.affiliation: The Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK.
authors.forename: Wojciech
authors.initials: W
authors.lastname: Niedzwiedz
authors.affiliation: School of Cancer Sciences, University of Birmingham, Birmingham B15 2TT, UK. Electronic address: g.s.stewart@bham.ac.uk.
authors.forename: Grant S
authors.initials: GS
authors.lastname: Stewart
mesh_terms: D018797:Cell Cycle Proteins / Q000235:genetics* / Q000378:metabolism*; D002460:Cell Line; D002470:Cell Survival; D004249:DNA Damage; D004265:DNA Helicases / Q000378:metabolism; D004261:DNA Replication; D004268:DNA-Binding Proteins / Q000378:metabolism; D015894:Genome, Human; D042822:Genomic Instability; D006367:HeLa Cells; D006801:Humans; D051135:Rad51 Recombinase / Q000235:genetics* / Q000378:metabolism*; D053484:RecQ Helicases / Q000378:metabolism
chemical_list: C524692:Bod1 protein, human; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C495153:RAD51 protein, human; D051135:Rad51 Recombinase; C097151:Bloom syndrome protein; D004265:DNA Helicases; D053484:RecQ Helicases; C464443:FBH1 protein, human