The concerted roles of FANCM and Rad52 in the protection of common fragile sites

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. Fanconi anemia core proteins have been linked to common fragile site stability. Here the authors shed light into the role of FANCM in common fragile site protection by suppressing double-strand break formation and mitotic recombination.

• Publication year

  2018

• Venue

  Nature Communications

• Publication date

  2018-07-18

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1038/s41467-018-05066-yPMID 30022024PMCID 6052092
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

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