Prof Bob Lahue

Professor of Molecular Genetics
SFI Principal Investigator

Research interests

  • DNA mutagenesis and repair
  • Trinucleotide repeat instability

Research overview

Our chromosomes constantly undergo the opposing forces of DNA mutagenesis and DNA repair. The balance between these two forces determines the genetic fate of our cells. Normally, DNA repair wins and our genome is kept healthy. If DNA repair fails, mutagenesis ensues, often with detrimental health effects.

One enigmatic exception is DNA containing trinucleotide repeats. Mutagenesis is incredibly frequent at trinucleotide repeats in families with certain hereditary neurological diseases. These site-specific expansions, or gains of triplet repeats, occur in cells that appear otherwise normal.

These features suggest that the usual rules governing mutagenesis and repair no longer apply, and that protein activities are altered when acting at triplet repeats.

We use genetics, biochemistry and cell biology to study triplet repeat expansions in cultured cells of the human central nervous system (Fig. 1).

The goal of this work is to the molecular mechanisms of how triplet repeats expand, and what protein factors are important in favoring or inhibiting the expansion process.

To date, the mismatch repair protein MutSß and the histone deacetylases HDAC3 and HDAC5 were identified as key factors that favor expansions. Their activities are counteracted by the DNA helicase RTEL1, which inhibits expansions. The activities of these proteins are currently under active investigation.

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Selected publications

  • Frizzell A, Nguyen JH, Petalcorin MI, Turner KD, Boulton SJ, Freudenreich CH, Lahue RS, RTEL1 inhibits trinucleotide repeat expansions and fragility. Cell Rep 6: 827-835 (2014)
  • Stevens JR, Lahue EE, Li GM, Lahue RS, Trinucleotide repeat expansions catalyzed by human cell-free extracts. Cell Res 23: 565-572 (2013)
  • Debacker K, Frizzell A, Gleeson O, Kirkham-McCarthy L, Mertz T, Lahue RS, Histone deacetylase complexes promote trinucleotide repeat expansions. PLoS Biol 10: e1001257 (2012)
  • Gannon AM, Frizzell A, Healy E, Lahue RS, MutSbeta and histone deacetylase complexes promote expansions of trinucleotide repeats in human cells. Nucleic Acids Res (2012)