Swuec, P; (2016) Structural Basis for the Activation of the Fanconi Anemia Interstrand Crosslink Repair Pathway. Doctoral thesis , UCL (University College London).

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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 are known to form a stable assembly. However, the molecular basis of FANCIFANCD2 modification 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, I have used structural electron microscopy, combined with crosslinking and mass spectrometry, to find that FANCB-FANCL-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 dimerisation interface. The data presented in this study led me to provide a model to explain how equivalent mono-ubiquitination of FANCI and FANCD2 occurs.

Type:	Thesis (Doctoral)
Title:	Structural Basis for the Activation of the Fanconi Anemia Interstrand Crosslink Repair Pathway
Event:	UCL (University College London)
Language:	English
UCL classification:	UCL UCL > Provost and Vice Provost Offices UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
URI:	https://discovery.ucl.ac.uk/id/eprint/1532940

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