FAN1 activity on asymmetric repair intermediates is mediated by an atypical monomeric virus-type replication-repair nuclease domain

Simon Pennell, Anne-Cécile Déclais, Jiejin Li, Lesley F Haire, Wioletta Berg, José W Saldanha, Ian A Taylor, John Rouse, David M J Lilley, Stephen J Smerdon

Research output: Contribution to journalArticlepeer-review

12 Citations (Scopus)
50 Downloads (Pure)

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.

Original languageEnglish
Pages (from-to)84-93
Number of pages10
JournalCell Reports
Volume8
Issue number1
Early online date26 Jun 2014
DOIs
Publication statusPublished - 10 Jul 2014

Bibliographical note

Copyright © 2014 The Authors.

Keywords

  • Amino Acid Sequence
  • Animals
  • Bacterial Proteins/chemistry
  • DNA Repair
  • DNA, Cruciform/metabolism
  • Endodeoxyribonucleases/chemistry
  • Exodeoxyribonucleases/chemistry
  • Holliday Junction Resolvases/chemistry
  • Humans
  • Mice
  • Molecular Sequence Data
  • Protein Binding
  • Protein Multimerization
  • Protein Structure, Tertiary
  • Pseudomonas aeruginosa/enzymology

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