Pathogenic repeat expansion links defective DNA repair to perturbed autophagy

The human genome is under continuous threat from environmental toxins and endogenous sources generated during normal metabolic activities. We have previously shown that failure to repair genomic breaks resulting from oxidative DNA breaks and those featuring protein-DNA cross-links lead to neurological disease in man, such as ataxia telangiectasia and spinocerebellar ataxia with axonal neuropathy. I will present and discuss data showing that genomic instability also underpins neurological demise associated with nucleotide repeat expansion. Accumulation of genomic breaks perturbs nuclear and mitochondrial gene transcription and reveals a new paradigm connecting DNA repair and autophagy with exciting opportunities for therapeutic intervention.