1. Cooperation of the FA and BRCA1/2 proteins in a common ICL repair pathway.
Cooperation of the FA and BRCA1/2 proteins in a common ICL repair pathway. Stalling of replication forks on DNA ICLs induces lesion recognition by the FANCM–FAAP24–MHF1/2 complex and subsequent recruitment of the FA core complex, which, in turn, recruits the mono-ubiquitinated FANCD2–FANCI to the ICL region. FANCM also initiates checkpoint response, which phosphorylates multiple FA proteins. Ubiquitinated FANCD2 acts as a landing pad for recruiting several nucleases to coordinate nucleolytic incisions. Unhooking the DNA leaves the cross-linked nucleotides tethered to the complementary strand, which are bypassed by translesion synthesis (TLS) polymerases. DNA incisions create a DSB, which is then repaired by HR. Downstream FA proteins, such as BRCA1, BRCA2, and PALB2, promote RAD51-dependent strand invasion and resolution of recombinant intermediates.
Panagiotis A. Konstantinopoulos et al. Cancer Discov 2015;5:
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