Investigating the function of atypical ubiquitylation in the DNA damage response

• Applicant: Professorin Dr. Petra Beli
• Subject Area: General Genetics and Functional Genome Biology ; Biochemistry ; Cell Biology
• Term: from 2013 to 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 241324827

Human cells are exposed to internal and external factors that induce different DNA lesions. Rapid recognition and repair of these lesions is essential for the maintenance of genome stability in all organisms. Protein ubiquitylation plays a central role in the regulation of the cellular response to DNA damage. Modification of DNA repair factors with K63- and K48-linked ubiquitylation has been shown to function in their coordinated recruitment to and removal from chromatin surrounding DNA lesions. However, it remained unclear whether other types of ubiquitin chains play a role in the DNA damage response. We have found that DNA damage induced by ultraviolet (UV) light radiation results in the rapid increase in the abundance of cellular K6-linked ubiquitylation. Induction of DNA double strand breaks, crosslinks or replication stress did not affect K6-linked ubiquitylation, suggesting a specific role for this atypical ubiquitylation in the cellular response to UV light. The functions and substrates of K6-linked ubiquitylation in human cells and in particular nuclear processes as well as the ubiquitin ligases that assemble this chain type remain poorly understood. In this project, we will combine mass spectrometry-based proteomics with biochemistry and cell biology to define the nuclear functions of K6-linked ubiquitylation. Towards this goal, we will identify the proteins that are modified with K6-linked ubiquitylation after UV light as well as the respective ubiquitin ligase that is responsible for assembling K6-linked ubiquitylation. Further studies will be performed to analyze the molecular consequence of ubiquitylation on substrate proteins as well as to characterize the functional role of K6-linked ubiquitylation in the cellular response to UV light. We anticipate that these studies will provide first insights into the role of atypical K6-linked ubiquitin chains in the regulation of nuclear proteins.

• DFG Programme: Independent Junior Research Groups