Ubiquitin and related proteins

Each cell has a large number of proteins at its disposal, which steer all life functions. Each protein takes on special tasks, but these can be altered through protein modifications. Small proteins of the ubiquitin family have the ability to modify the way other proteins function. Ubiquitin owes its name to the fact that it is found universally in all eukaryotic organisms. When ubiquitin is conjugated to a target protein – a process known as ubiquitylation – it usually “earmarks” the protein for degradation by the proteasome (a large cellular protease).

Protein degradation

Stefan Jentsch pioneered our understanding of the function of ubiquitin and related proteins. With his colleagues, the German researcher was the first to discover and to clone genes that encode ubiquitin-activating and conjugating enzymes (E1, E2 and E3). They have also identified a new factor of this enzyme cascade, they called E4, which enhances ubiquitylation reactions.
Furthermore, Stefan Jentsch and his team provided the first evidence that the degradation of proteins of the endoplasmic reticulum (a sub-compartment of eukaryotic cells) is mediated by the ubiquitin-proteasome system. This particular pathway is of high medical importance as it is linked to cystic fibrosis.

Stefan Jentsch’s group also characterized the function of the chaperone protein Cdc48/p97 as an enzyme that extracts ubiquitylated proteins from their environment.

DNA repair

Early studies indicated that ubiquitin functions as a label for degradation. However, Stefan Jentsch showed that ubiquitin also fulfils other functions. In 1987, together with Alexander Varshavsky, he discovered that it plays a key part in DNA repair. Thanks to this research, we now know that besides triggering degradation, ubiquitylation also controls protein transport and cell signalling, and a large number of functions in the nucleus of eukaryotic cells, in particular DNA repair.
The medical implications could be significant since it has been shown that defective ubiquitylation is behind various pathologies including breast cancer, as well as various rare but serious genetic disorders such as Fanconi anemia and Xeroderma pigmentosum.

From cancer to the evolution of species

DNA is fragile and particularly vulnerable to damage. For example, exposure to the ultraviolet spectrum of sunlight, ionizing radiation or even certain chemical products may result in mutations and cause cancer. Damaged DNA can also lead to broken chromosomes, resulting in cell death or the genesis of tumours.
Fortunately our organism has a number of ways of repairing damaged DNA and of safeguarding the genome. Stefan Jentsch and co-workers identified one of these processes, the “PCNA switch”. PCNA (Proliferating Cell Nuclear Antigen) is a ring-shaped protein around the DNA, and functions as a co-factor for DNA polymerases, the enzymes that duplicate the genome prior to cell division. Modification of PCNA comes into play if the DNA to be replicated is damaged, and avoids a situation where the duplication process stops or chromosomes are broken.
Stefan Jentsch and his team discovered how the “PCNA switch” functions. They found that PCNA can be modified by either a single ubiquitin molecule (“mono-ubiquitylation”), by a string of several ubiquitin molecules attached to each other thereby forming a “poly-ubiquitin chain” (“poly-ubiquitylation”), or by the ubiquitin-related SUMO protein (Small Ubiquitin-like MOdifier) (see figure).
When PCNA is subject to mono-ubiquitylation, it recruits dedicated DNA polymerases that can operate even on damaged DNA. However, these enzymes are “sloppy”, i.e. they can make errors and thereby produce mutations. PCNA poly-ubiquitylation on the other hand activates a different pathway that seems more complex, but does not create mutations. Finally, PCNA SUMOylation blocks a third, more dangerous rescue pathway, which is initiated when the first two are inactive, but is more hazardous as it comports greater risks of broken chromosomes.
The “PCNA switch” in fact decides which of the three DNA-damage tolerance pathways is to be used to best protect the DNA. Although the second “error-free” pathway seems to be the most reasonable, mono-ubiquitylation is also of value although it causes mutations through UV-light. It is particularly useful for generating certain antibodies, and is also fundamental for the evolution of species since without mutations new species would never occur. This means that the role of this biological switch extends well beyond medical considerations and that the scope of Stefan Jentsch’s discoveries surpasses the field of molecular and cellular biology.

Fig. The PCNA switch
Duplication of the genome (replication) before cell division involves the ring-shaped protein PCNA (yellow) around the DNA (not shown). When the genome duplication machinery encounters damaged DNA, replication stops and PCNA will be modified either by mono-ubiquitylation (a single molecule of ubiquitin, shown in orange, binds to it), or by poly-ubiquitylation.
Mono-ubiquitylation promotes the recruitment of enzymes that promote an “error-prone” pathway, which can lead to mutations of the DNA. Poly-ubiquitylation promotes an “error-free” pathway. SUMOylation (i.e. binding a SUMO protein, shown in blue), occurs even when there is no damage to the DNA. It prevents homologous recombination between the sister chromatids during replication.

Professor Stefan Jentsch

Max-Planck Institute of Biochemistry
Department of Molecular Cell Biology
Professor Stefan Jentsch, Director
Am Klopferspitz 18
82152 Martinsried, Germany

Tel.: +49 89 8578 3000 (direct : 3010)

jentsch@biochem.mpg.de
http://www.biochem.mpg.de/jentsch/Jentsch.html