Dangerous liaisons: Fanconi anemia and toxic nonhomologous end joining in DNA crosslink repair

Abstract

The proper choice of repair pathway is critical to tolerating various types of DNA damage. In a recent issue of Molecular Cell, Adamo et al. (2010), along with a second report (Pace et al., 2010), describe how the Fanconi anemia (FA) pathway is involved in preventing aberrant DNA repair. These studies suggest a potentially significant new opportunity for the treatment of FA.

Figure 1.. Opportunities for NHEJ Factors to Impact DNA Interstrand Crosslink Repair

(A and B) DNA interstrand crosslinks (ICLs) block DNA replication, causing collapse of DNA replication forks and recruitment of Fanconi anemia (FA) gene products. The FA complex mediates ICL repair and inhibits the activity of nonhomologous end-joining (NHEJ) proteins such as Ku, which can promote genomic instability through ““toxic NHEJ.”” In the absence of FA gene products, Ku can potentially bind double-strand breaks formed (A) after incision of DNA at ICLs by endonucleases, or (B) after replication fork regression. Replication fork regression may be required to allow access of endonucleases to process ICLs. In either case, binding of Ku to double-stranded breaks could prevent completion of repair.