Processing of Interstrand Cross-Links in Mammalian Cells

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The cell's ability to repair damage to its DNA is critical for its survival, and accordingly it has evolved a variety of mechanisms to remove the corruptive alterations to which the genetic material is subject. In addition, in multicellular organisms, maintenance of genomic integrity is critical in successful tumor suppression, and mutant alleles of DNA repair genes have been shown to confer an inherited predisposition to cancer. Compounds that introduce interstrand crosslinks (ICLs) in DNA are both important anticancer agents as well as possible mutagens and carcinogens. However, the mechanisms of repair of these lesions in mammalian cells are poorly understood. Using biochemical approaches we have identified a number of proteins that are required for processing of psoralen ICLs in vitro. These proteins include Erccl, Xpf, Msh2, Msh3, RPA, PCNA, and a complex involving the human homolog of PSO4. The goals of this proposal are to extend our biochemical studies to the identification of additional factors that are required for processing psoralen ICLs in vitro, to determine if the in vitro processing of other classes of ICLs is mediated by the same or different components, and to determine the relevance of the observed in vitro processing of ICLs by directly monitoring their removal in vivo.