title: FANCD2, FANCJ and BRCA2 cooperate to promote replication fork recovery independently of the Fanconi Anemia core complex.
abstract: Fanconi Anemia (FA) is an inherited multi-gene cancer predisposition syndrome that is characterized on the cellular level by a hypersensitivity to DNA interstrand crosslinks (ICLs). To repair these lesions, the FA pathway proteins are thought to act in a linear hierarchy: Following ICL detection, an upstream FA core complex monoubiquitinates the central FA pathway members FANCD2 and FANCI, followed by their recruitment to chromatin. Chromatin-bound monoubiquitinated FANCD2 and FANCI subsequently coordinate DNA repair factors including the downstream FA pathway members FANCJ and FANCD1/BRCA2 to repair the DNA ICL. Importantly, we recently showed that FANCD2 has additional independent roles: it binds chromatin and acts in concert with the BLM helicase complex to promote the restart of aphidicolin (APH)-stalled replication forks, while suppressing the firing of new replication origins. Here, we show that FANCD2 fulfills these roles independently of the FA core complex-mediated monoubiquitination step. Following APH treatment, nonubiquitinated FANCD2 accumulates on chromatin, recruits the BLM complex, and promotes robust replication fork recovery regardless of the absence or presence of a functional FA core complex. In contrast, the downstream FA pathway members FANCJ and BRCA2 share FANCD2's role in replication fork restart and the suppression of new origin firing. Our results support a non-linear FA pathway model at stalled replication forks, where the nonubiquitinated FANCD2 isoform - in concert with FANCJ and BRCA2 - fulfills a specific function in promoting efficient replication fork recovery independently of the FA core complex.
authors: a Department of Biochemistry; Molecular Biology and Biophysics ; University of Minnesota ; Minneapolis , MN USA.
authors: Maya
authors: M
authors: Raghunandan
authors: Indrajit
authors: I
authors: Chaudhury
authors: Stephanie L
authors: SL
authors: Kelich
authors: Helmut
authors: H
authors: Hanenberg
authors: Alexandra
authors: A
authors: Sobeck
mesh_terms: D016590:Aphidicolin / Q000494:pharmacology; D024682:BRCA2 Protein / Q000378:metabolism*; D050976:Basic-Leucine Zipper Transcription Factors / Q000378:metabolism*; D002460:Cell Line; D002843:Chromatin / Q000378:metabolism; D004261:DNA Replication / Q000187:drug effects; D052236:Fanconi Anemia Complementation Group D2 Protein / Q000378:metabolism*; D051856:Fanconi Anemia Complementation Group Proteins / Q000378:metabolism*; D006801:Humans; D008954:Models, Biological; D046912:Multiprotein Complexes / Q000378:metabolism*; D050505:Mutant Proteins / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D020033:Protein Isoforms / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D054875:Ubiquitination / Q000187:drug effects
chemical_list: C102108:BACH1 protein, human; D024682:BRCA2 Protein; D050976:Basic-Leucine Zipper Transcription Factors; D002843:Chromatin; D052236:Fanconi Anemia Complementation Group D2 Protein; D051856:Fanconi Anemia Complementation Group Proteins; D046912:Multiprotein Complexes; D050505:Mutant Proteins; D020033:Protein Isoforms; D016590:Aphidicolin
keywords: FA pathway; FANCD1/BRCA2; FANCD2; FANCD2 monoubiquitination; FANCJ; Fanconi Anemia; replication fork recovery