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The FA Core Complex Contains a Homo-dimeric Catalytic Module for the Symmetric Mono-ubiquitination of FANCI-FANCD2.

Authors
  • Swuec, Paolo1
  • Renault, Ludovic1
  • Borg, Aaron2
  • Shah, Fenil3
  • Murphy, Vincent J3
  • van Twest, Sylvie3
  • Snijders, Ambrosius P2
  • Deans, Andrew J3
  • Costa, Alessandro4
  • 1 Macromolecular Machines Laboratory, Clare Hall Laboratory, The Francis Crick Institute, Blanche Lane, South Mimms, EN6 3LD, UK.
  • 2 Mass Spectrometry Proteomics and Metabolomics, Clare Hall Laboratory, The Francis Crick Institute, Blanche Lane, South Mimms, EN6 3LD, UK.
  • 3 Genome Stability Unit, St. Vincent's Institute of Medical Research, 9 Princes St Fitzroy, Victoria, VIC 3065, Australia. , (Australia)
  • 4 Macromolecular Machines Laboratory, Clare Hall Laboratory, The Francis Crick Institute, Blanche Lane, South Mimms, EN6 3LD, UK. Electronic address: [email protected]
Type
Published Article
Journal
Cell Reports
Publisher
Elsevier
Publication Date
Jan 17, 2017
Volume
18
Issue
3
Pages
611–623
Identifiers
DOI: 10.1016/j.celrep.2016.11.013
PMID: 27986592
Source
Medline
Keywords
License
Unknown

Abstract

Activation of the main DNA interstrand crosslink repair pathway in higher eukaryotes requires mono-ubiquitination of FANCI and FANCD2 by FANCL, the E3 ligase subunit of the Fanconi anemia core complex. FANCI and FANCD2 form a stable complex; however, the molecular basis of their ubiquitination is ill defined. FANCD2 mono-ubiquitination by FANCL is stimulated by the presence of the FANCB and FAAP100 core complex components, through an unknown mechanism. How FANCI mono-ubiquitination is achieved remains unclear. Here, we use structural electron microscopy, combined with crosslink-coupled mass spectrometry, to find that FANCB, FANCL, and FAAP100 form a dimer of trimers, containing two FANCL molecules that are ideally poised to target both FANCI and FANCD2 for mono-ubiquitination. The FANCC-FANCE-FANCF subunits bridge between FANCB-FANCL-FAAP100 and the FANCI-FANCD2 substrate. A transient interaction with FANCC-FANCE-FANCF alters the FANCI-FANCD2 configuration, stabilizing the dimerization interface. Our data provide a model to explain how equivalent mono-ubiquitination of FANCI and FANCD2 occurs.

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