Welcome to the O'Connell Lab

The O’Connell lab is focused on understanding the biochemical mechanisms of prokaryotic immunity and RNA-mediated gene regulation, and on the development of new tools to study these processes. We are particularly interested in two distinct areas of research:

1. How RNA-targeting Cas13-containing CRISPR-Cas systems and their membrane-associated proteins function together to enhance anti-phage defense with an eye towards the discovery of new molecular tools and understanding the virus-host arms race, which has implications for vaccine development, phage therapy and antimicrobe drug resistance. We have discovered that in addition to containing RNA-guided nucleases, many CRISPR-Cas systems encode diverse accessory proteins that may help to bolster antiphage defense. Using a combination of cryo–electron microscopy, genetic, and biochemical approaches, our lab discovered that Csx28, an accessory protein found in some CRISPR-Cas systems, forms an inner membrane–localized octameric pore Upon Cas13 activation by viral messenger RNAs, Csx28 assists in protecting against sustained viral infection by helping to depolarize the inner membrane and slow metabolism. These findings expand the complexity of CRISPR-Cas–based defense systems and offer the potential for new molecular technologies (published in Science 2023). We are now expanding these efforts to look at other membrane-protein containing CRISPR-Cas systems, as well as other anti-phage defense systems
2. How the tRNA modification N4-acetylcytidine (ac4C) is important for protein synthesis during human development, as we discovered loss of this modification results in a syndromic form of intellectual disability associated with developmental delay, behavioral abnormalities, hearing loss and facial dysmorphism. We are currently trying to further understand biochemically how loss of this chemical group on a subset of tRNAs results in the phenotype we see in patients, with the hope finding treatment strategies in the future.

We use a range of interdisciplinary approaches including molecular biology, protein and RNA biochemistry, CRISPR gene editing, CRISPR RNA-targeting strategies, structural biology, mass spectrometry, high-throughput sequencing, and bioinformatics to understand these processes.

Please see our publications for more details.

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