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ERC

SULTENG Result In Brief

Project ID: 201177
Funded under: FP7-IDEAS-ERC
Country: Israel

Detox system and DNA repair – under examination

Interestingly, proteins such as proliferating cell nuclear antigen (PCNA) and cytosolic sulfotransferases (SULTs) are ubiquitous in living organisms. EU funded researchers used protein engineering, biochemical and genetic approaches to study their action.
Detox system and DNA repair – under examination
A key process in all living beings is DNA replication and repair and PCNA is critical for mediating this. SULTs are enzymes that are a crucial part of the detoxification system that work by varying sulphating capacity. Any functional disruptions in these proteins is detrimental to good health and longevity.

Scientists of the SULTENG (Protein engineering for the study of detoxification enzymes and hub proteins) project worked on deciphering the roles of these poorly understood proteins. They generated and characterised PCNA mutants with increased affinities for key proteins that are part of the DNA replication machinery. They also produced SULT1A1 and SULT1E1 mutants with increased specificities.

A key development is the establishment of an experimental system for monitoring the co-evolution of PCNA-partner interactions in fungi species. A major advantage of this system is that it can be used to study other biological networks.

Researchers found that severe phenotypic defects occurred in vivo with an increase in PCNA-protein interaction affinities for the progression of DNA replication and repair. More importantly, deleting part of the PCNA-protein interaction network was not as catastrophic as an imbalance between different PCNA-partner interaction affinities. This has significant implications in drug design.

Co-evolution studies revealed that PCNA-partner interactions are tightly co-evolved in fungi species and are diverged into two distinct groups. Hybrids of these groups were functionally incompatible, indicating that such co-evolution can create functional reproductive barriers for gene transfer between species. In other words, PCNA-partner interaction networks can promote and fix speciation.

Despite detoxification processes being so crucial for health, the mechanism of action of SULT isoforms is still a mystery. Researchers explored the molecular mechanisms involved in the broad specificity and substrate inhibition of the SULT isoforms - SULT1A1 and SULT1E1. Study outcomes enabled them to determine new SULT1A1 structures in complex with different acceptors and identify many residues involved in controlling specificity. Results indicate that even subtle structural changes in these enzymes caused dramatic changes in specificity.

Project activities have innumerable applications in biomedicine. A better understanding of PCNA and SULT function could prove useful in diverse areas such as drug design and development, cancer susceptibility, predicting response to xenobiotics, reproduction and development.

Related information

Keywords

Detoxification, enzyme, PCNA, SULT, protein engineering, DNA replication, co-evolution, speciation, specificity
Record Number: 183052 / Last updated on: 2016-07-19
Domain: Biology, Medicine