Abstract
The Fanconi Anemia (FA) pathway consists of proteins involved in repairing DNA damage, including interstrand cross-links (ICLs). The pathway contains an upstream multiprotein core complex that mediates the monoubiquitylation of the FANCD2 and FANCI heterodimer, and a downstream pathway that converges with a larger network of proteins with roles in homologous recombination and other DNA repair pathways. Selective killing of cancer cells with an intact FA pathway but deficient in certain other DNA repair pathways is an emerging approach to tailored cancer therapy. Inhibiting the FA pathway becomes selectively lethal when certain repair genes are defective, such as the checkpoint kinase ATM. Inhibiting the FA pathway in ATM deficient cells can be achieved with small molecule inhibitors, suggesting that new cancer therapeutics could be developed by identifying FA pathway inhibitors to treat cancers that contain defects that are synthetic lethal with FA.
Highlights
Fanconi anemia is a rare genetic disease featuring characteristic developmental abnormalities, a progressive pancytopenia, genomic instability, and predisposition to cancer [1, 2]
The breast cancer susceptibility and Fanconi proteins FANCD1/BRCA2, the partner of BRCA2 (PALB2/FANCN), a helicase associated with BRCA1 (FANCJ/BACH1), and several newly identified components including FAN1, FANCO/RAD51C, and FANCP/SLX4 [13,14,15,16,17] participate in the pathway to respond to and repair DNA damage
Inhibition of the Fanconi Anemia (FA) pathway could occur at any point in the multistep FA protein network, but a key predictive readout for FA function and resistance to interstrand cross-links (ICLs) is the monoubiquitylation of FANCD2 [11, 55]
Summary
Fanconi anemia is a rare genetic disease featuring characteristic developmental abnormalities, a progressive pancytopenia, genomic instability, and predisposition to cancer [1, 2]. The FA pathway contains a multiprotein core complex, including at least twelve proteins that are required for the monoubiquitylation of the FANCD2/FANCI protein complex and for other functions that are not well understood [3,4,5,6]. The breast cancer susceptibility and Fanconi proteins FANCD1/BRCA2, the partner of BRCA2 (PALB2/FANCN), a helicase associated with BRCA1 (FANCJ/BACH1), and several newly identified components including FAN1, FANCO/RAD51C, and FANCP/SLX4 [13,14,15,16,17] participate in the pathway to respond to and repair DNA damage (for review, see [5]). The latter approach depends on inhibiting the FA pathway in tumor cells that are defective for a secondary pathway required for survival in the absence of the FA pathway
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