2. Academic Validation
  3. DNA repair. Mechanism of DNA interstrand cross-link processing by repair nuclease FAN1

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

  • Science. 2014 Nov 28;346(6213):1127-30. doi: 10.1126/science.1258973.
Renjing Wang 1,  Nicole S Persky 1,  Barney Yoo 2,  Ouathek Ouerfelli 2,  Agata Smogorzewska 3,  Stephen J Elledge 4,  Nikola P Pavletich 5
Affiliations

Affiliations

  • 1 Structural Biology Program and Howard Hughes Medical Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
  • 2 Molecular Pharmacology and Chemistry Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
  • 3 Laboratory of Genome Maintenance, The Rockefeller University, New York, NY 10065, USA.
  • 4 Department of Genetics and Howard Hughes Medical Institute, Harvard Medical School, Boston, MA 02115, USA. Division of Genetics, Brigham and Women's Hospital, Boston, MA 02115, USA.
  • 5 Structural Biology Program and Howard Hughes Medical Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. [email protected].
PMID: 25430771 DOI: 10.1126/science.1258973
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.

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