The functions and regulation of ubiquitin and ubiquitin-like modifications

Reactive oxygen species (ROS) are produced as the by-product
of cellular processes. High levels of ROS are also a vital
defense mechanism against pathogens (e.g. Candida albicans),
whereas low levels regulate important cell signalling pathways.
However, high levels of ROS can cause oxidative stress and cell
damage, leading to age-related diseases and disorders. Therefore,
it is important to understand how eukaryotic cells sense and respond
to stresses such as high ROS levels to underpin the development of
approaches to improve health and wellbeing across the human life
course (BBSRC priority area of Bioscience for an Integrated
Understanding of Health).Recent work in model yeast revealed
that oxidation of catalytic cysteine residues within conserved
antioxidants (e.g. thioredoxin system) plays a key role in
ROS responses. Interestingly, other enzymes which utilize catalytic
cysteine residues, such as those involved in ubiquitin (Ub) and
ubiquitin-like (Ubl) modification (e.g. SUMO, NEDD), are also
oxidized in eukaryotes. For example, oxidation of the Ub E2
enzyme Cdc34 leads to cell cycle arrest in yeast in response to
oxidative stress. Ub/Ubl modifications regulate the cell cycle,
development and DNA repair, and alterations are linked to common
human diseases. Therefore, the project aim is to build upon this
research to understand the functions and regulation of Ub/Ubl
modifications and their links with stress responses and human
disease.The project will provide opportunities to gain experience
of multidisciplinary skills, including use of experimental systems such
as Saccharomyces cerevisiae and mammalian cells, genetics
(including genetic screens), biochemistry (including analyses
of protein modifications), cell biology, microscopy, and
standard molecular biology techniques. In addition, techniques to
investigate the regulation of the cell cycle will potentially be applied.