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Title: Studies of the Fanconi anemia pathway
Author: Liang, Chih-Chao
ISNI:       0000 0004 6494 3155
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2016
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The human genome is constantly challenged by various DNA damages, where several DNA damage repair pathways are required to guard the integrity of our genome. One type of lesion is DNA interstrand crosslink (ICL), which prevents any cellular process requiring the separation of the two DNA strands, and could lead to missegregation of chromosomes and mitotic catastrophe. The Fanconi anemia DNA damage repair pathway (FA pathway) has been shown to be responsible for the repair of ICLs. To date, there are 21 FA proteins identified that participate in the repair process. Among them, the FANCD2/FANCI heterodimer plays an important role in orchestrating the recruitment of the downstream repair proteins. Upon the appearance of ICLs, the FANCD2/FANCI complex is monoubiquitinated, and localised to the sites of DNA lesion. While the molecular mechanism of how the FA pathway operates is emerging, there are still questions remaining, such as if there is a sensor for ICLs being able to activate the FA pathway, or the timing of the recruitment of the FANCD2/FANCI heterodimer to damaged chromatin. In this thesis, first, I will describe the identification and characterisation of a novel ICL sensor protein, UHRF1, and its role in the activation of the FA pathway. Second, I will describe the first cryo-EM structure of the human FANCD2/FANCI complex, which led to the discovery of the functionally important Tower domain in the C-terminal of FANCD2. In addition, our work reveals that the FANCD2/FANCI complex is recruited to damaged chromatin prior to its monoubiquitination.
Supervisor: Cohn, Martin Sponsor: Goodger Scholarship ; Taiwanese Government
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available