New Mechanisms that Control FACT Histone Chaperone and Transcription-mediated Genome Stability

The Role of deubiquitinating enzymes (DUBs) in transcription, replication and genome integrity is not one that has been extensively researched. OTU DUBs are a particular class of enzyme with very little known about them.OTUD5 is a cysteine protease in the OTU family responsible to processing lysine 48 and lysine 63 ubiquitin chains. Recently, it has been implicated in to play a role in transcription through its binding partner UBR5. OTUD5 has also been shown to interact with proteins such as PDCD5 and p53, potentially have great importance in cell fate. In this study, I describe new discovered functions for OTUD5 in regards to transcriptional regulation at double strand breaks through a novel interaction with the histone chaperone FACT complex and the downstream effects of OTUD5 has by preventing Transcription-Replication Conflict (TRC). I provide evidence for the UBR5/OTUD5/FACT complex and how they bind to each other: OTUD5 binds UBR5 through its disordered N-terminal tail while the UIM of OTUD5 binds directly to SPT16. I describe a new pathway where FACT/OTUD5 interact with histone deacetylases 1 and 2 (HDAC1/2) to coordinate transcriptional repression both at double strand breaks and at the replication for in order to maintain genomic integrity