Decoding the noncanonical polyubiquitin chains using chemical approaches The ubiquitin system is crucial for the regulation of a wide range of cellular and organismal functions essential for the human health. Although our knowledge of the ubiquitin system initially stems from the investigation into proteasome-mediated protein degradation, it has become clear that ubiquitination is also indispensible for many non-proteolytic functions. Many noncanonical ubiquitin chains are associated with cellular functions other than protein degradation. The K63-linked polyubiquitin chain in DNA damage tolerance has been found to be signal for the eukaryotic error-free lesion bypass. However, little is known as to how this signal regulates the DNA damage tolerance pathways. The downstream proteins that decode the K63- polyubiquitin signals on PCNA still need to be identified. In order to decipher the diverse cellular roles of polyubiquitination, chemical approaches of generating polyubiquitinated proteins and noncanonical ubiquitin chains with defined structure and length are needed. This will lead to the discovery of the downstream reader proteins in DNA damage tolerance and other important cellular processes. It will also enable in-depth biochemical and biophysical characterizations of the recognition of noncanonical polyubiquitin chains by the reader proteins. This will broaden our understanding of the many biological processes regulated by ubiquitination and furnish new pathways and targets amenable for therapeutic intervention.
Decoding the noncanonical polyubiquitin chains using chemical approaches Narrative The ubiquitin proteasome system provides a vast number of targets that can be exploited for therapeutic interventions. Our understanding of the complex signaling mechanisms through the many different forms of ubiquitin modifications, particularly on the noncanonical polyubiquitin chains, is very limited. A understanding of the function and recognition of the noncanonical polyubiquitin chains in the biological processes will not only deepen our understanding of many essential cellular processes, but also open doors to new therapeutic interventions by modulating the signal transduction through ubiquitination.
