Professor Keith Caldecott and Professor Kevin Staras
The identification of novel molecular mechanisms and therapeutic avenues in DNA damage-induced hereditary neurological disease
Genetic defects in the repair of DNA single-strand breaks result in human hereditary diseases that span a spectrum of neuropathology from progressive neurodegeneration in the mildest diseases to neurodevelopmental defects and seizures in the most severe1,2. Recently, we identified a novel molecular mechanism that underpins such diseases, in which ‘programmed’ DNA breakage in gene enhancers and/or hyperactivity of the SSB sensor protein PARP1 disrupts the expression of genes critical for normal neural function3–6. In this project, the successful applicant will extend and exploit these and other exciting recent discoveries using a combination of molecular, cellular, and neurophysiological techniques that include CRISPR-Cas9 gene editing, iPSC-derived human neurons, and ex vivo/in vivo mouse models of DNA break-induced synaptic dysfunction.
- Caldecott, K. W., Ward, M. E. & Nussenzweig, A. The threat of programmed DNA damage to neuronal genome integrity and plasticity. Nat Genet 54, 115–120 (2022).
- Caldecott, K. W. Single-strand break repair and genetic disease. Nat Rev Genet 9, 619–631 (2008).
- Wu, W. et al. Neuronal enhancers are hotspots for DNA single-strand break repair. Nature 593, 440–444 (2021).
- Hoch, N. C. et al. XRCC1 mutation is associated with PARP1 hyperactivation and cerebellar ataxia. Nature 541, 87–91 (2017).
- Komulainen, E. et al. Parp1 hyperactivity couples DNA breaks to aberrant neuronal calcium signalling and lethal seizures. EMBO Rep 22, e51851 (2021).
- Adamowicz, M. et al. XRCC1 protects transcription from toxic PARP1 activity during DNA base excision repair. Nat Cell Biol 23, 1287–1298 (2021).