FANCD2 and CtIP Cooperate to Repair DNA Interstrand Crosslinks

• DOI: 10.1016/j.celrep.2014.03.069
• Publication Date: 2014-05-01T15:45:11Z
• Authors: Olga Murina; Christine von Aesch; Ufuk Karakus; Lorenza P. Ferretti; Hella A. Bolck; Kay Hänggi; Alessandro A. Sar...
• Keywords: 0301 basic medicine; Endodeoxyribonucleases; DNA Repair; QH301-705.5; Ubiquitin; Fanconi Anemia Complementation Group D2 Protein; 10061 Institute of Molecular Cancer Research; Nuclear Proteins; DNA; Transfection; 03 medical and health sciences; Fanconi Anemia; HEK293 Cells; 1300 General Biochemistry, Genetics and Molecular Biology; Cell Line, Tumor; Chromosomal Instability; 570 Life sciences; biology; Humans; DNA Breaks, Double-Stranded; Biology (General); DNA Cleavage; Carrier Proteins

The resolution of DNA interstrand crosslinks (ICLs) requires a complex interplay between several processes of DNA metabolism, including the Fanconi anemia (FA) pathway and homologous recombination (HR). FANCD2 monoubiquitination and CtIP-dependent DNA-end resection represent key events in FA and HR activation, respectively, but very little is known about their functional relationship. Here, we show that CtIP physically interacts with both FANCD2 and ubiquitin and that monoubiquitinated FANCD2 tethers CtIP to damaged chromatin, which helps channel DNA double-strand breaks generated during ICL processing into the HR pathway. Consequently, CtIP mutants defective in FANCD2 binding fail to associate with damaged chromatin, which leads to increased levels of nonhomologous end-joining activity and ICL hypersensitivity. Interestingly, we also observe that CtIP depletion aggravates the genomic instability in FANCD2-deficient cells. Thus, our data indicate that FANCD2 primes CtIP-dependent resection during HR after ICL induction but that CtIP helps prevent illegitimate recombination in FA cells.