Abstract
Fanconi anemia (FA) is a devastating hereditary disease characterized by bone marrow failure (BMF) and acute myeloid leukemia (AML). As FA-deficient cells are hypersensitive to DNA interstrand crosslinks (ICLs), ICLs are widely assumed to be the lesions responsible for FA symptoms. Here, we show that FA-mutated cells are hypersensitive to persistent replication stress and that FA proteins play a role in the break-induced-replication (BIR)-like pathway for fork restart. Both the BIR-like pathway and ICL repair share almost identical molecular mechanisms of 53BP1-BRCA1-controlled signaling response, SLX4- and FAN1-mediated fork cleavage and POLD3-dependent DNA synthesis, suggesting that the FA pathway is intrinsically one of the BIR-like pathways. Replication stress not only triggers BMF in FA-deficient mice, but also specifically induces monosomy 7, which is associated with progression to AML in patients with FA, in FA-deficient cells.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Aneuploidy
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Animals
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Bone Marrow Failure Disorders / etiology
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Cell Line, Transformed
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Chickens
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Chromosome Breakage
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Chromosome Deletion
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Chromosomes, Human, Pair 7 / genetics
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DNA Polymerase III / physiology
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DNA Replication* / genetics
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Disease Progression
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Fanconi Anemia / genetics*
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Fanconi Anemia / metabolism
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Fanconi Anemia Complementation Group Proteins / deficiency
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Fanconi Anemia Complementation Group Proteins / genetics
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Fanconi Anemia Complementation Group Proteins / physiology*
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Female
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HCT116 Cells
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HEK293 Cells
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Humans
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Hydroxyurea / pharmacology
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Leukemia, Myeloid, Acute / genetics
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Male
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Models, Genetic
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Species Specificity
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Tumor Suppressor p53-Binding Protein 1 / physiology
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Ubiquitin-Protein Ligases / physiology
Substances
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Fanconi Anemia Complementation Group Proteins
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TP53BP1 protein, human
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Tumor Suppressor p53-Binding Protein 1
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BRAP protein, human
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Ubiquitin-Protein Ligases
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POLD3 protein, human
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DNA Polymerase III
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Hydroxyurea