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Cellular DNA is constitutively engaged in close non-covalent interactions with numerous DNA-binding proteins. DNA is tightly packaged by histones and dynamic interactions between DNA and protein factors are required for efficient transcription, replication and maintenance of the genome. Exposure to chemical crosslinking agents can cause any of these proteins to become covalently trapped on DNA, generating bulky DNA-protein crosslinks (DPCs) that interfere with DNA metabolism and thereby threaten genome integrity. Crosslinking agents, like reactive oxygen species and reactive aldehydes, are constantly generated as by-products of normal cellular metabolism, making the formation of DPCs unavoidable. In addition, several chemotherapeutic agents used in the clinic exert their toxicity by generating DPCs. Despite their abundance and relevance to human health, very little is known about the repair mechanisms that remove DPCs.