| Literature DB >> 27986592 |
Paolo Swuec1, Ludovic Renault1, Aaron Borg2, Fenil Shah3, Vincent J Murphy3, Sylvie van Twest3, Ambrosius P Snijders2, Andrew J Deans3, Alessandro Costa4.
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.Entities:
Keywords: DNA repair; Fanconi anemia; cryo-electron microscopy; interstrand crosslink; mono-ubiquitination; ubiquitin ligase
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Year: 2016 PMID： 27986592 PMCID： PMC5266791 DOI： 10.1016/j.celrep.2016.11.013
Source DB: PubMed Journal: Cell Rep Impact factor: 9.995