Fanconi-like crosslink repair in yeast

DNA damaging agents such as nitrogen mustard [1,2], formaldehyde [3], and cisplatin [4] generate many lesions that inhibit proper DNA replication and transcription. One such lesion, the interstrand crosslink (ICL), covalently links two complementary DNA strands and prevents their separation. Importantly, since both strands are damaged, an undamaged template strand is not available for repair. Due to these blocks and repair challenges, ICLs are considered one of the most toxic DNA lesions. It is estimated that the presence of just one unrepaired ICL is sufficient to kill yeast or bacteria [5] and approximately 40 unrepaired ICLs can kill mammalian cells [6]. As a result of this high cytotoxicity, crosslinking agents are common anticancer agents [7]. Outside of chemotherapies, ICLs can be induced by exposures in the environment [8] and byproducts of normal metabolic processes [9,10]. Thus, a clearer understanding of the mechanisms of ICL repair will inform our knowledge of both normal and cancer cells. This article and another recent review [11] describe novel findings in yeast that provide insight into the mechanisms of eukaryotic ICL repair.Cells have the capacity to repair ICLs through highly complex DNA repair mechanisms. ICL repair in the prokaryotic system is relatively well defined. In Escherichia coli, nucleotide excision repair (NER) creates incisions on each side of the ICL. The resulting short oligonucleotide is attached through the ICL, but is displaced from the helix, revealing a gap. The gap is filled in by homologous recombination (HR) or translesion bypass synthesis (TLS), and the displaced oligonucleotide/ICL adduct is removed by NER [12].In lower eukaryotes, defects in most known DNA repair pathways result in ICL sensitivity suggesting that eukaryotic mechanisms are much more complex, involve multiple repair pathways, and can occur in multiple phases of the cell cycle. Several recent reviews address this complexity in detail [13-23]. In the budding y