title: FAN1 activity on asymmetric repair intermediates is mediated by an atypical monomeric virus-type replication-repair nuclease domain.
abstract: FAN1 is a structure-selective DNA repair nuclease with 5' flap endonuclease activity, involved in the repair of interstrand DNA crosslinks. It is the only eukaryotic protein with a virus-type replication-repair nuclease ("VRR-Nuc") "module" that commonly occurs as a standalone domain in many bacteria and viruses. Crystal structures of three representatives show that they structurally resemble Holliday junction resolvases (HJRs), are dimeric in solution, and are able to cleave symmetric four-way junctions. In contrast, FAN1 orthologs are monomeric and cleave 5' flap structures in vitro, but not Holliday junctions. Modeling of the VRR-Nuc domain of FAN1 reveals that it has an insertion, which packs against the dimerization interface observed in the structures of the viral/bacterial VRR-Nuc proteins. We propose that these additional structural elements in FAN1 prevent dimerization and bias specificity toward flap structures.
authors: Division of Molecular Structure, MRC National Institute for Medical Research, The Ridgeway, London NW7 1AA, UK. Electronic address: spennel@nimr.mrc.ac.uk.
authors: Simon
authors: S
authors: Pennell
authors: CRUK Nucleic Acids Structure Research Group, College of Life Sciences, University of Dundee, Dundee DD1 5EH, UK.
authors: Anne-Cécile
authors: AC
authors: Déclais
authors: Division of Molecular Structure, MRC National Institute for Medical Research, The Ridgeway, London NW7 1AA, UK.
authors: Jiejin
authors: J
authors: Li
authors: Division of Molecular Structure, MRC National Institute for Medical Research, The Ridgeway, London NW7 1AA, UK.
authors: Lesley F
authors: LF
authors: Haire
authors: Division of Molecular Structure, MRC National Institute for Medical Research, The Ridgeway, London NW7 1AA, UK.
authors: Wioletta
authors: W
authors: Berg
authors: Division of Mathematical Biology, MRC National Institute for Medical Research, London NW7 1AA, UK.
authors: José W
authors: JW
authors: Saldanha
authors: Division of Molecular Structure, MRC National Institute for Medical Research, The Ridgeway, London NW7 1AA, UK.
authors: Ian A
authors: IA
authors: Taylor
authors: MRC Protein Phosphorylation Unit, College of Life Sciences, University of Dundee, Dundee DD1 5EH, UK.
authors: John
authors: J
authors: Rouse
authors: CRUK Nucleic Acids Structure Research Group, College of Life Sciences, University of Dundee, Dundee DD1 5EH, UK.
authors: David M J
authors: DM
authors: Lilley
authors: Division of Molecular Structure, MRC National Institute for Medical Research, The Ridgeway, London NW7 1AA, UK.
authors: Stephen J
authors: SJ
authors: Smerdon
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001426:Bacterial Proteins / Q000737:chemistry* / Q000378:metabolism; D004260:DNA Repair; D045566:DNA, Cruciform / Q000378:metabolism*; D004706:Endodeoxyribonucleases / Q000737:chemistry* / Q000378:metabolism; D005090:Exodeoxyribonucleases / Q000737:chemistry* / Q000378:metabolism; D045565:Holliday Junction Resolvases / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D064251:Multifunctional Enzymes; D011485:Protein Binding; D055503:Protein Multimerization; D017434:Protein Structure, Tertiary; D011550:Pseudomonas aeruginosa / Q000201:enzymology
chemical_list: D001426:Bacterial Proteins; D045566:DNA, Cruciform; D064251:Multifunctional Enzymes; D004706:Endodeoxyribonucleases; D005090:Exodeoxyribonucleases; C551063:FAN1 protein, human; C000596972:Fan1 protein, mouse; D045565:Holliday Junction Resolvases