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Title: Characterisation of novel phosphorylation sites on FANCD2 and their role in the Fanconi anaemia pathway
Author: Lopez-Martinez, David
ISNI:       0000 0004 7653 4607
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2018
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Interstrand crosslinks (ICLs) are a highly deleterious form of DNA damage because they link the two strands of DNA, blocking replication, transcription and chromosome segregation. At the center of ICL repair is the FANCD2/FANCI complex, recruitment of which onto the ICL is a critical step for repair. Monoubiquitination of both FANCD2 and FANCI lead to their retention on chromatin and is essential for subsequent repair. However, recent evidence shows that FANCD2 monoubiquitination takes place only after recruitment to DNA (Liang et al., 2016). If the monoubiquitination is taking place after recruitment to DNA, the question of how the recruitment to DNA is regulated remains open. Our objective is to study the role of FANCD2 phosphorylation in regulating recruitment to DNA and repair. We report a new cluster of phosphosites on FANCD2 whose phosphorylation by CK2 inhibits FANCD2 activation. Specifically, phosphorylation of FANCD2 in this cluster abrogates recruitment to ICLs and inhibits monoubiquitination in vitro and in vivo. Furthermore, phosphorylation of the cluster leads to a dramatic reduction in affinity of the FANCD2/FANCI complex towards DNA, which in turn blocks its monoubiquitination and the activation of the FA pathway. We describe a new regulatory mechanism where FANCD2 must be dephosphorylated prior to the loading of the FANCD2/FANCI complex onto DNA and activation of the FA pathway. This step could act as a safeguard against spurious activation of repair in the absence of damage.
Supervisor: Cohn, Martin Sponsor: Medical Research Council
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: DNA repair ; Genomic instability