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Quality control of gene expression: mechanisms for recognition and elimination of nonsense mRNA

Objective

Analogous to quality control checks along the assembly line in industrial manufacturing processes, cells possess multiple quality control systems that ensure accurate expression of the genetic information throughout the intricate chain of biochemical reactions. “Nonsense-mediated mRNA decay” (NMD) represents a quality control mechanism that recognizes and degrades mRNAs of which the protein coding sequence is truncated by the presence of a premature termination codon (PTC). By eliminating these defective mRNAs with crippled protein-coding capacity, NMD substantially reduces the synthesis of potentially deleterious truncated proteins. Given that 30 % of all known disease-causing mutations in humans lead to the production of a nonsense mRNA, NMD serves as an important modulator of the clinical manifestations of genetic diseases, and manipulating NMD therefore represents a promising strategy for future therapies of many genetic disorders. However, the underlying molecular mechanisms of NMD are currently not well understood. One goal of our research is to understand at the molecular level how PTCs are recognized and distinguished from correct termination codons and how this recognition of nonsense mRNAs subsequently triggers their rapid degradation. In addition to triggering NMD, we have recently discovered that PTCs in certain immunoglobulin genes can also lead to the transcriptional silencing of the corresponding gene. We now search for the biological relevance of this novel quality control mechanism termed “nonsense-mediated transcriptional gene silencing” (NMTGS) and want to identify the involved molecules and their interactions. Using mainly mammalian cell cultures, we study the effect on the expression of engineered NMD and NMTGS reporter genes upon various treatments of the cells. State-of-the-art biochemical and molecular biology techniques are employed with the goal to further our understanding of these processes and their regulation at the molecular level.

Field of science

  • /natural sciences/biological sciences/genetics and heredity/mutation
  • /natural sciences/biological sciences/molecular biology
  • /natural sciences/biological sciences/biochemistry/biomolecules/proteins

Call for proposal

ERC-2007-StG
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Funding Scheme

ERC-SG - ERC Starting Grant

Host institution

UNIVERSITAET BERN
Address
Hochschulstrasse 6
3012 Bern
Switzerland
Activity type
Higher or Secondary Education Establishments
EU contribution
€ 1 300 000
Principal investigator
Oliver Mühlemann (Dr.)
Administrative Contact
Maddalena Tognola (Ms.)

Beneficiaries (1)

UNIVERSITAET BERN
Switzerland
EU contribution
€ 1 300 000
Address
Hochschulstrasse 6
3012 Bern
Activity type
Higher or Secondary Education Establishments
Principal investigator
Oliver Mühlemann (Dr.)
Administrative Contact
Maddalena Tognola (Ms.)