Characterization of UHRF2 (RNF107) as a novel sensor for DNA ICLs in the Fanconi Anemia Pathway

Thesis

The Fanconi Anemia (FA) pathway is important for repairing interstrand crosslinks (ICLs) between the Watson-Crick strands of the DNA helix. An initial and essential stage in the repair process is the detection of the ICL. In a previous study, UHRF1 was identified as an ICL sensor in humans, it was shown that downstream repair factors were not recruited normally to the ICL in the absence of UHRF1. However, the mechanism underlying this process was unknown. Here, we report the identification of UHRF2, a paralogue of UHRF1, as an ICL sensor protein. We show that UHRF2 cooperates with UHRF1, to ensure recruitment of FANCD2 to the ICL. We show that a direct protein-protein interaction with FANCD2 is formed via the SRA domain of UHRF1, and a direct interaction is formed between UHRF2 and UHRF1. Moreover, we demonstrate that the essential monoubiquitination of FANCD2 is stimulated by UHRF1/UHRF2, by mediating its retention on chromatin. Taken together, we uncover the mechanism of FANCD2 activation by monoubiquitination via recruitment and retention at ICLs dependent on an interaction with UHRF1/UHRF2.

Authors: Motnenko, A

• DOI: 10.5287/ora-rdwnybrom
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford