UBIQUITIN SIGNALING PATHWAY: from basic mechanisms to human diseases

     Ubiquitin is a small signaling protein that covalently attaches to lysine, N-terminal methionine, sometime even serine or threonine residues of its substrates through its C-terminal glycine residue. This ubiquitylation process is mediated by three enzymes: a ubiquitin activating enzyme (E1), a ubiquitin conjugating enzyme (E2) and a ubiquitin ligase (E3). One of the major consequences of ubiquitylation is protein turnover by the 26S proteasome, which is the primary pathway that regulates the levels of many short-lived proteins in eukaryotes. The substrate specificity of ubiquitylation is controlled by the E3s. Mutations in genes involving protein ubiquitylation are often with deleterious consequences on cellular function. Dysregulation of the ubiquitin signaling pathway has been associated with numerous human diseases, such as cancer, autoimmune and neurodegenerative diseases.

1. Protein ubiquitylation and DNA damage responses

     Emerging evidence indicates that protein ubiquitylation plays indispensable roles in the DNA damage responses. Previously, we found that the Cullin/RING ubiquitin ligases mediate DNA damage checkpoint control and DNA rereplication prevention. Currently, we are focusing on the roles of protein ubiquitylation in control of R-loop dynamics. R-loops are three-stranded nucleic acid structures formed between a RNA/DNA hybrid and a displaced single-stranded DNA on genomes. They are abundant structures and occupy up to 5% of mammalian genomes. Biologically, R-loops play very important roles in transcription, epigenetic gene regulation, DNA replication, cell cycle, DNA damage and immune responses. However, dysregulation of R-loop formation and clearance have been linked to several human diseases, especially cancer due to genomic instability, the hallmark of cancer. Therefore, comprehending molecular mechanisms of R-loop formation and clearance will significantly improve our understanding of tumorigenesis and identify novel therapeutics to cure cancer.

2. Cullin/RING ubiquitin ligases and cancer signaling pathways

     Many genetic mutations have been identified in genes related to protein ubiquitylation or their cognate substrates. Therefore, ubiquitylation-related genes could be either oncogenes or tumor suppressors. Cullin/RING ubiquitin ligases (CRLs) constitute a super-family of multi-subunit E3 complexes. They consist of a ring finger protein, a cullin scaffold, an optional linker and a receptor subunit that usually has dozens of family members. CRLs control ubiquitylation of many important oncogenes and tumor suppressors, such as Cdc25A, c-Myc, c-Jun and p27. We will continue our studies on the roles of CRLs in cancer signaling pathways.

3. Ubiquitination and inflammation

We have found that p97, an ATPase, plays an essential role in cytokine-induced IκBα post-ubiquitinational regulation. We also found that two co-factors of p97, Ufd1L and NPL4, assist p97 to present the ubiquitinated IκBα to the 26S proteasome. This post-ubiquitinational regulation of IκBα is crucial to cytokine-induced NF-κB activation that is the center of inflammation response. We will continue our previous studies in the roles of protein ubiquitination and inflammation.