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The Beckwith Lab studies the dynamic genome. We focus on a virus-like transposable element (a “jumping gene”) called Ty1 in the budding yeast Saccharomyces. By studying molecular mechanisms utilized in Ty1 replication and how Ty1 is restricted to prevent uncontrolled replication, we seek to both advance our basic understanding of transposons and viruses as well as identify targets for novel therapeutics. Our approach is led by genetics and informed by bioinformatics, using interdisciplinary techniques from biochemistry, cell biology, and genomics.
Project 1: An interchangeable prion-like domain is required for Ty1 retrotransposition
We have discovered a disordered protein sequence in Ty1 that is similar to sequences implicated in transmissible and neurodegenerative mammalian diseases (e.g., Alzheimer's, Parkinson's, Huntington's, Creutzfeld-Jakob disease). This prion-like domain is required for Ty1 to build virus-like particles (VLPs). Our work suggests a mechanism for nucleating VLP assembly that may be widespread across transposons and viruses and establishes an in vivo platform to study disordered protein sequences involved in neurodegeneration and other diseases using the extensive genetic toolkit developed for Ty1 in yeast.
Our current work focuses on understanding the Ty1 prion-like domain’s sequence constraints and biophysical contribution to transposition, characterizing related disordered sequences from other transposons and viruses, and exploring cellular and environmental crosstalk processed through the prion-like domain to influence Ty1 transposition.
Related publications:
Beckwith S, Nomberg E, Newman A, Taylor J, Guerrero-Ferreira R, Garfinkel D. An interchangeable prion-like domain is required for Ty1 retrotransposition. Proceedings of the National Academy of Sciences. 2023. doi.org/10.1073/pnas.2303358120.
Project 2: The molecular mechanism of Ty1 restriction
Uncontrolled replication of Ty1 retrotransposons can be deleterious to the host and is restricted by a self-encoded protein called p22. To prevent excessive Ty1 replication and genomic damage, p22 disrupts virus-like particle (VLP) function by interaction with the Ty1 Gag protein. Disrupting VLP assembly prevents reverse transcription and retrotransposition. We uncovered the molecular basis of p22 restriction by solving the crystal structure of a minimal fragment of p22. Our data suggest how p22 can function in restriction through a blocking-of-assembly mechanism to inhibit VLP assembly by creating dead-end intermediates in the assembly pathway.
Our current work tests predictions of our blocking-of-assembly model. We are elucidating the molecular determinants of restriction specificity, which may inform the rational design of blocking-of-assembly inhibitors for disease-relevant retrotransposons, retroviruses, and domesticated capsid genes in mammalian genomes.
Related publications:
Cottee M, Beckwith S, Letham S, Kim S, Young G, Stoye J, Garfinkel D, Taylor A. Structure of a Ty1 Restriction Factor Reveals the Molecular Basis of Transposition Copy Number Control. Nature Communications. 2021. doi:10.1038/s41467-021-25849-0.
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