DNA replication, transcription and translation provide the foundation for life itself. Together, these three processes ensure the inheritance of our genome and the faithful expression of our genetic code. To preserve the integrity of this code, it is essential that these processes are carried out with remarkable precision. Sporadic errors are unavoidable though, and these errors reveal how important biological fidelity is for organismal health. For example, errors that occur during DNA replication contribute to carcinogenesis and errors that occur during translation contribute to protein aggregation. Interestingly, transcription errors can contribute to both of these processes, but they are primarily linked to protein aggregation. For example, in patients with non-familial cases of Alzheimer’s disease transcription errors in the UBB and β-APP gene generate toxic versions of the Aβ and ubiquitin-B protein that contribute to disease progression. Random transcription errors are also a source of proteotoxic stress. While studying yeast cells that display error-prone transcription we found that these errors tend to compromise the structural integrity of proteins, which results in widespread protein misfolding. Individually, these misfolded proteins have little effect on cellular health, but together they can overload the protein quality control machinery and prevent the degradation of highly toxic proteins that are normally targets for this machinery. For example, TDP-43 (amyotrophic lateral sclerosis, ALS), Aβ1-42 (Alzheimer’s disease), Htt103Q (Huntington’s disease), and RNQ1 (a prion) all cause greater aggregation and toxicity in cells that display error prone transcription compared to WT cells. Thus, transcription errors do not only generate highly specific disease-related peptides, such as toxic Aβ and ubiquitin-B, they also provide the conditions that allow these proteins to survive inside cells and seed aggregates. As a result, it will be important to learn more about the molecular mechanisms that control the fidelity of transcription, because these mechanisms could directly affect the age of onset, progression and severity of diseases caused by protein misfolding. Our lab is in the process of identifying these mechanisms in yeast, worms, flies and mice using the co-called circle-sequencing assay.
Vermulst M, Denney AS, Lang MJ, Hung CW, Madden V, Gauer J, Wolfe KJ, Summers DW, Schleit J, Sutphin GL, Haroon S, Holczbauer A, Cyr D, Kaeberlein M, Strathern JN, Duncan MC and Erie D. Transcription errors induce proteotoxic stress and shorten cellular lifespan. (Nature Communications, 6, article 8065, Aug. 25, 2015)
J.-F. Gout, Weiyi Li, C. Fritsch, A. Li, S. Haroon, L. Singh, D. Hua, H. Fazelina, Z. Smith, S, . Seeholzer, K. Thomas, M. Lynch, M. Vermulst. The landscape of transcription errors in eukaryotic organisms. Science Advances, published online, October 20th 2017, Vol. 3. No. 10, e1701484. PMID: 29062891
C. Fritsch, JF Gout, M. Vermulst. Transcription errors: A new horizon for mutation research. J Vis Exp. 2018 Sep 13;(139). doi: 10.3791/57731