title: The Fanconi Anemia Pathway Protects Genome Integrity from R-loops.
abstract: Co-transcriptional RNA-DNA hybrids (R loops) cause genome instability. To prevent harmful R loop accumulation, cells have evolved specific eukaryotic factors, one being the BRCA2 double-strand break repair protein. As BRCA2 also protects stalled replication forks and is the FANCD1 member of the Fanconi Anemia (FA) pathway, we investigated the FA role in R loop-dependent genome instability. Using human and murine cells defective in FANCD2 or FANCA and primary bone marrow cells from FANCD2 deficient mice, we show that the FA pathway removes R loops, and that many DNA breaks accumulated in FA cells are R loop-dependent. Importantly, FANCD2 foci in untreated and MMC-treated cells are largely R loop dependent, suggesting that the FA functions at R loop-containing sites. We conclude that co-transcriptional R loops and R loop-mediated DNA damage greatly contribute to genome instability and that one major function of the FA pathway is to protect cells from R loops.
authors.affiliation: Centro Andaluz de Biología Molecular y Medicina Regenerativa CABIMER, Universidad de Sevilla, Seville, Spain.
authors.forename: María L
authors.initials: ML
authors.lastname: García-Rubio
authors.affiliation: Centro Andaluz de Biología Molecular y Medicina Regenerativa CABIMER, Universidad de Sevilla, Seville, Spain.
authors.forename: Carmen
authors.initials: C
authors.lastname: Pérez-Calero
authors.affiliation: Centro Andaluz de Biología Molecular y Medicina Regenerativa CABIMER, Universidad de Sevilla, Seville, Spain.
authors.forename: Sonia I
authors.initials: SI
authors.lastname: Barroso
authors.affiliation: Centro Andaluz de Biología Molecular y Medicina Regenerativa CABIMER, Universidad de Sevilla, Seville, Spain.
authors.forename: Emanuela
authors.initials: E
authors.lastname: Tumini
authors.affiliation: Centro Andaluz de Biología Molecular y Medicina Regenerativa CABIMER, Universidad de Sevilla, Seville, Spain.
authors.forename: Emilia
authors.initials: E
authors.lastname: Herrera-Moyano
authors.affiliation: Instituto de Biomedicina de Sevilla-Hospital Virgen del Rocío, Seville, Spain.
authors.forename: Iván V
authors.initials: IV
authors.lastname: Rosado
authors.affiliation: Centro Andaluz de Biología Molecular y Medicina Regenerativa CABIMER, Universidad de Sevilla, Seville, Spain.
authors.forename: Andrés
authors.initials: A
authors.lastname: Aguilera
mesh_terms: D000818:Animals; D024682:BRCA2 Protein / Q000235:genetics*; D004247:DNA / Q000737:chemistry / Q000235:genetics; D004249:DNA Damage / Q000235:genetics; D004260:DNA Repair / Q000235:genetics; D004261:DNA Replication / Q000235:genetics; D052217:Fanconi Anemia Complementation Group A Protein / Q000235:genetics*; D052236:Fanconi Anemia Complementation Group D2 Protein / Q000235:genetics*; D042822:Genomic Instability / Q000235:genetics*; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D012313:RNA / Q000737:chemistry / Q000235:genetics
chemical_list: D024682:BRCA2 Protein; C498471:FANCA protein, human; C499905:FANCD2 protein, human; D052217:Fanconi Anemia Complementation Group A Protein; D052236:Fanconi Anemia Complementation Group D2 Protein; D012313:RNA; D004247:DNA