Abstract
Common fragile sites (CFSs) are prone to chromosomal breakage and are hotspots for chromosomal rearrangements in cancer cells. We uncovered a novel function of Fanconi anemia (FA) protein FANCM in the protection of CFSs that is independent of the FA core complex and the FANCI-FANCD2 complex. FANCM, along with its binding partners FAAP24 and MHF1/2, is recruited to CFS-derived structure-prone AT-rich sequences, where it suppresses DNA double-strand break (DSB) formation and mitotic recombination in a manner dependent on FANCM translocase activity. Interestingly, we also identified an indispensable function of Rad52 in the repair of DSBs at CFS-derived AT-rich sequences, despite its nonessential function in general homologous recombination (HR) in mammalian cells. Suppression of Rad52 expression in combination with FANCM knockout drastically reduces cell and tumor growth, suggesting a synthetic lethality interaction between these two genes, which offers a potential targeted treatment strategy for FANCM-deficient tumors with Rad52 inhibition.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Apoptosis Regulatory Proteins / genetics
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Apoptosis Regulatory Proteins / metabolism
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Cell Line, Tumor
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Chromosome Fragile Sites*
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Colonic Neoplasms / genetics*
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Colonic Neoplasms / metabolism
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Colonic Neoplasms / pathology
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Colonic Neoplasms / therapy
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DNA / genetics
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DNA / metabolism
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DNA Breaks, Double-Stranded
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DNA Helicases / antagonists & inhibitors
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DNA Helicases / genetics*
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DNA Helicases / metabolism
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism
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Fanconi Anemia Complementation Group Proteins
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Female
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Gene Expression Regulation, Neoplastic*
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HCT116 Cells
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HEK293 Cells
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Humans
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Injections, Subcutaneous
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Mice
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Mice, Nude
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism
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RNA, Small Interfering / genetics
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RNA, Small Interfering / metabolism
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Rad52 DNA Repair and Recombination Protein / antagonists & inhibitors
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Rad52 DNA Repair and Recombination Protein / genetics*
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Rad52 DNA Repair and Recombination Protein / metabolism
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Recombinational DNA Repair*
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Signal Transduction
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Tumor Suppressor Proteins / genetics
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Tumor Suppressor Proteins / metabolism
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Xenograft Model Antitumor Assays
Substances
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Apoptosis Regulatory Proteins
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CENPS protein, human
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CENPX protein, human
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DNA-Binding Proteins
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FAAP24 protein, human
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Fanconi Anemia Complementation Group Proteins
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Nuclear Proteins
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RAD52 protein, human
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RNA, Small Interfering
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Rad52 DNA Repair and Recombination Protein
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Tumor Suppressor Proteins
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DNA
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FANCM protein, human
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DNA Helicases