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

Hailong Wang, Shibo Li, Joshua Oaks, Jianping Ren, Lei Li and Xiaohua Wu ()
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Hailong Wang: Capital Normal University
Shibo Li: The Scripps Research Institute
Joshua Oaks: The Scripps Research Institute
Jianping Ren: Capital Normal University
Lei Li: The University of Texas M.D. Anderson Cancer Center
Xiaohua Wu: The Scripps Research Institute

Nature Communications, 2018, vol. 9, issue 1, 1-14

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-05066-y

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