title: Impaired TIP60-mediated H4K16 acetylation accounts for the aberrant chromatin accumulation of 53BP1 and RAP80 in Fanconi anemia pathway-deficient cells.
abstract: To rescue collapsed replication forks cells utilize homologous recombination (HR)-mediated mechanisms to avoid the induction of gross chromosomal abnormalities that would be generated by non-homologous end joining (NHEJ). Using DNA interstrand crosslinks as a replication barrier, we investigated how the Fanconi anemia (FA) pathway promotes HR at stalled replication forks. FA pathway inactivation results in Fanconi anemia, which is associated with a predisposition to cancer. FANCD2 monoubiquitination and assembly in subnuclear foci appear to be involved in TIP60 relocalization to the chromatin to acetylates histone H4K16 and prevents the binding of 53BP1 to its docking site, H4K20Me2. Thus, FA pathway loss-of-function results in accumulation of 53BP1, RIF1 and RAP80 at damaged chromatin, which impair DNA resection at stalled replication fork-associated DNA breaks and impede HR. Consequently, DNA repair in FA cells proceeds through the NHEJ pathway, which is likely responsible for the accumulation of chromosome abnormalities. We demonstrate that the inhibition of NHEJ or deacetylase activity rescue HR in FA cells.
authors.affiliation: Univ Paris-Sud, Laboratoire «Stabilité Génétique et Oncogenèse», Equipe Labellisée La Ligue Contre Le Cancer, 94805 Villejuif, France CNRS - UMR 8200, 94805 Villejuif, France Gustave Roussy, 94805 Villejuif, France.
authors.forename: Emilie
authors.initials: E
authors.lastname: Renaud
authors.affiliation: Univ Paris-Sud, Laboratoire «Stabilité Génétique et Oncogenèse», Equipe Labellisée La Ligue Contre Le Cancer, 94805 Villejuif, France CNRS - UMR 8200, 94805 Villejuif, France Gustave Roussy, 94805 Villejuif, France.
authors.forename: Aurelia
authors.initials: A
authors.lastname: Barascu
authors.affiliation: Univ Paris-Sud, Laboratoire «Stabilité Génétique et Oncogenèse», Equipe Labellisée La Ligue Contre Le Cancer, 94805 Villejuif, France CNRS - UMR 8200, 94805 Villejuif, France Gustave Roussy, 94805 Villejuif, France filippo.rosselli@gustaveroussy.fr.
authors.forename: Filippo
authors.initials: F
authors.lastname: Rosselli
mesh_terms: D000107:Acetylation; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002843:Chromatin / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D059766:DNA End-Joining Repair; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D005199:Fanconi Anemia / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D052236:Fanconi Anemia Complementation Group D2 Protein / Q000235:genetics / Q000378:metabolism; D051548:Histone Acetyltransferases / Q000235:genetics / Q000378:metabolism*; D056488:Histone Chaperones; D006657:Histones / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D000074443:Lysine Acetyltransferase 5; D000076228:MRE11 Homologue Protein; D016685:Mitomycin / Q000494:pharmacology; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D000071857:Tumor Suppressor p53-Binding Protein 1; D054875:Ubiquitination
chemical_list: D002352:Carrier Proteins; D002843:Chromatin; D004268:DNA-Binding Proteins; C499905:FANCD2 protein, human; D052236:Fanconi Anemia Complementation Group D2 Protein; D056488:Histone Chaperones; D006657:Histones; D047908:Intracellular Signaling Peptides and Proteins; C121766:MRE11 protein, human; D009687:Nuclear Proteins; C498301:TP53BP1 protein, human; D000071857:Tumor Suppressor p53-Binding Protein 1; C466234:UIMC1 protein, human; D016685:Mitomycin; D051548:Histone Acetyltransferases; C098489:KAT5 protein, human; D000074443:Lysine Acetyltransferase 5; D000076228:MRE11 Homologue Protein