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Mechanism of DNA interstrand cross-link processing by repair nuclease FAN1

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Science  28 Nov 2014:
Vol. 346, Issue 6213, pp. 1127-1130
DOI: 10.1126/science.1258973

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Abstract

DNA interstrand cross-links (ICLs) are highly toxic lesions associated with cancer and degenerative diseases. ICLs can be repaired by the Fanconi anemia (FA) pathway and through FA-independent processes involving the FAN1 nuclease. In this work, FAN1-DNA crystal structures and biochemical data reveal that human FAN1 cleaves DNA successively at every third nucleotide. In vitro, this exonuclease mechanism allows FAN1 to excise an ICL from one strand through flanking incisions. DNA access requires a 5′-terminal phosphate anchor at a nick or a 1- or 2-nucleotide flap and is augmented by a 3′ flap, suggesting that FAN1 action is coupled to DNA synthesis or recombination. FAN1’s mechanism of ICL excision is well suited for processing other localized DNA adducts as well.

Staggered incisions unhook DNA crosslinks

Mutations that covalently link the two stands of DNA together, known as interstrand cross-links (ICLs), can wreak havoc with the many processes that need to separate the DNA strands to read the genome. For example, ICLs are commonly generated in the skin by exposure to UV. Wang et al. determined the crystal structure of the ICL repair exonuclease FAN1 bound to a branched segment of DNA that mimics an intermediate on the ICL repair pathway. The enzyme anchors itself at a cut end of DNA and then cleaves successively at three nucleotide intervals, a pattern ideal for unhooking the ICL. FAN1 seems to have evolved to act, at least in part, at sites coupled to DNA synthesis or homologous recombination.

Science, this issue p. 1127

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