DNA interstrand crosslinkers, a chemically diverse group of compounds which also induce alkylation of bases and
DNA intrastrand crosslinks, are extensively utilized for
cancer therapy. Understanding the cellular response to DNA damage induced by these agents is critical for more effective utilization of these compounds and for the identification of novel therapeutic targets. Importantly, the repair of
DNA interstrand crosslinks (ICLs) involves many distinct DNA repair pathways, including nucleotide excision repair, translesion synthesis (TLS), and homologous recombination (HR). Additionally,
proteins implicated in the pathophysiology of the multigenic disease
Fanconi anemia (FA) have a role in the repair of ICLs that is not well understood. Cells from FA patients are hypersensitive to agents that induce ICLs, therefore FA
proteins are potentially novel therapeutic targets. Here we will review current research directed at identifying FA genes and understanding the function of FA
proteins in DNA damage responses. We will also examine interactions of FA
proteins with other repair
proteins and pathways, including signaling networks, which are potentially involved in ICL repair. Potential approaches to the modulation of FA
protein function to enhance therapeutic outcome will be discussed. Also, mutation of many genes that encode
proteins involved in ICL repair, including FA genes, increases susceptibility to
cancer. A better understanding of these pathways is therefore critical for the design of individualized
therapies tailored to the genetic profile of a particular
malignancy. For this purpose, we will also review evidence for the association of mutation of FA genes with
cancer in non-FA patients.