title: The Fanconi Anemia Pathway Maintains Genome Stability by Coordinating Replication and Transcription.
abstract: DNA replication stress can cause chromosomal instability and tumor progression. One key pathway that counteracts replication stress and promotes faithful DNA replication consists of the Fanconi anemia (FA) proteins. However, how these proteins limit replication stress remains largely elusive. Here we show that conflicts between replication and transcription activate the FA pathway. Inhibition of transcription or enzymatic degradation of transcription-associated R-loops (DNA:RNA hybrids) suppresses replication fork arrest and DNA damage occurring in the absence of a functional FA pathway. Furthermore, we show that simple aldehydes, known to cause leukemia in FA-deficient mice, induce DNA:RNA hybrids in FA-depleted cells. Finally, we demonstrate that the molecular mechanism by which the FA pathway limits R-loop accumulation requires FANCM translocase activity. Failure to activate a response to physiologically occurring DNA:RNA hybrids may critically contribute to the heightened cancer predisposition and bone marrow failure of individuals with mutated FA proteins.
authors.affiliation: Department of Oncology, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DS, UK.
authors.forename: Rebekka A
authors.initials: RA
authors.lastname: Schwab
authors.affiliation: Department of Oncology, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DS, UK.
authors.forename: Jadwiga
authors.initials: J
authors.lastname: Nieminuszczy
authors.affiliation: Genome Stability Unit, St. Vincent's Institute, Fitzroy, VIC 3065, Australia.
authors.forename: Fenil
authors.initials: F
authors.lastname: Shah
authors.affiliation: Department of Oncology, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DS, UK.
authors.forename: Jamie
authors.initials: J
authors.lastname: Langton
authors.affiliation: Department of Biochemistry, University of Oxford, Oxford OX1 3QU, UK.
authors.forename: David
authors.initials: D
authors.lastname: Lopez Martinez
authors.affiliation: Department of Biochemistry, University of Oxford, Oxford OX1 3QU, UK.
authors.forename: Chih-Chao
authors.initials: CC
authors.lastname: Liang
authors.affiliation: Department of Biochemistry, University of Oxford, Oxford OX1 3QU, UK.
authors.forename: Martin A
authors.initials: MA
authors.lastname: Cohn
authors.affiliation: Medical Research Council Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DS, UK.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Gibbons
authors.affiliation: Genome Stability Unit, St. Vincent's Institute, Fitzroy, VIC 3065, Australia.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Deans
authors.affiliation: Department of Oncology, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DS, UK. Electronic address: wojciech.niedzwiedz@imm.ox.ac.uk.
authors.forename: Wojciech
authors.initials: W
authors.lastname: Niedzwiedz
mesh_terms: D000818:Animals; D004249:DNA Damage; D004265:DNA Helicases / Q000235:genetics / Q000378:metabolism*; D004261:DNA Replication; D051856:Fanconi Anemia Complementation Group Proteins / Q000235:genetics / Q000378:metabolism*; D042822:Genomic Instability; D006367:HeLa Cells; D006801:Humans; D007938:Leukemia / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D009692:Nucleic Acid Heteroduplexes / Q000235:genetics / Q000378:metabolism*
chemical_list: D051856:Fanconi Anemia Complementation Group Proteins; D009692:Nucleic Acid Heteroduplexes; C518295:FANCM protein, human; D004265:DNA Helicases