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

Swuec, P.; Renault, L.L.R.; Borg, A.; Shah, F.; Murphy, V.J.; Twest, S. van; ... ; Costa, A. (2017)

Article / Letter to editor

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.

• DNA repair
• Fanconi anemia
• cryo-electron microscopy
• interstrand crosslink
• mono-ubiquitination
• ubiquitin ligase

• All authors: Swuec, P.; Renault, L.L.R.; Borg, A.; Shah, F.; Murphy, V.J.; Twest, S. van; Snijders, A.P.; Deans, A.J.; Costa, A.
• Date: 2017-01-17
• Journal: Cell Reports
• Volume: 18
• Issue: 3
• Pages: 611 - 623
• DOI: doi:10.1016/j.celrep.2016.11.013
• Link: https://www.sciencedirect.com/science/article/pii/S2211124716315546?via=...