title: Monoubiquitinated Fanconi anemia D2 (FANCD2-Ub) is required for BCR-ABL1 kinase-induced leukemogenesis.
abstract: Fanconi D2 (FANCD2) is monoubiquitinated on K561 (FANCD2-Ub) in response to DNA double-strand breaks (DSBs) to stimulate repair of these potentially lethal DNA lesions. FANCD2-Ub was upregulated in CD34+ chronic myeloid leukemia (CML) cells and in BCR-ABL1 kinase-positive cell lines in response to elevated levels of reactive oxygen species (ROS) and DNA cross-linking agent mitomycin C. Downregulation of FANCD2 and inhibition of FANCD2-Ub reduced the clonogenic potential of CD34+ CML cells and delayed BCR-ABL1 leukemogenesis in mice. Retarded proliferation of BCR-ABL1 positive FANCD2-/- leukemia cells could be rescued by FANCD2 expression. BCR-ABL1 positive FANCD2-/- cells accumulated more ROS-induced DSBs in comparison with BCR-ABL1 positive FANCD2+/+ cells. Antioxidants diminished the number of DSBs and enhanced proliferation of BCR-ABL1 positive FANCD2-/- cells. Expression of wild-type FANCD2 and FANCD2(S222A) phosphorylation-defective mutant (deficient in stimulation of intra-S phase checkpoint, but proficient in DSB repair), but not FANCD2(K561R) monoubiquitination-defective mutant (proficient in stimulation of intra-S phase checkpoint, but deficient in DSB repair) reduced the number of DSBs and facilitated proliferation of BCR-ABL1 positive FANCD2-/- cells. We hypothesize that FANCD2-Ub has an important role in BCR-ABL1 leukemogenesis because of its ability to facilitate the repair of numerous ROS-induced DSBs.
authors.affiliation: Department of Microbiology and Immunology, Temple University School of Medicine, Philadelphia, PA 19140, USA.
authors.forename: M
authors.initials: M
authors.lastname: Koptyra
authors.forename: T
authors.initials: T
authors.lastname: Stoklosa
authors.forename: G
authors.initials: G
authors.lastname: Hoser
authors.forename: E
authors.initials: E
authors.lastname: Glodkowska-Mrowka
authors.forename: I
authors.initials: I
authors.lastname: Seferynska
authors.forename: A
authors.initials: A
authors.lastname: Klejman
authors.forename: J
authors.initials: J
authors.lastname: Blasiak
authors.forename: T
authors.initials: T
authors.lastname: Skorski
mesh_terms: D000818:Animals; D002460:Cell Line; D053903:DNA Breaks, Double-Stranded; D052236:Fanconi Anemia Complementation Group D2 Protein / Q000502:physiology*; D016044:Fusion Proteins, bcr-abl / Q000235:genetics*; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000209:etiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D016685:Mitomycin / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D054875:Ubiquitination
chemical_list: D052236:Fanconi Anemia Complementation Group D2 Protein; D017382:Reactive Oxygen Species; D016685:Mitomycin; D016044:Fusion Proteins, bcr-abl