Gomez-Herreros et al. TDP2 protects transcription from abortive topoisomerase activity and is required for normal neural function. Nat Genet. 2014 May;46(5):516-21. doi: 10.1038/ng.2929. Epub 2014 Mar 23.
Gomez-Herreros et al identify homozygous mutations in TDP2 as a new cause of intellectual disability, by performing homozygosity mapping and exome sequencing in a consanguineous Irish family with three brothers suffering from developmental delay accompanied by refractory epilepsy and progressive ataxia.
The molecular pathophysiological mechanism proposed by the authors is particularly interesting. In the course of its function of unwinding DNA strands in order to facilitate transcription, topoisomerase II normally creates double-strand breaks. Most of these breaks are transient, being quickly repaired by the same enzyme. The ones that remain are repaired by tyrosyl DNA phosphodiesterase-2, encoded by TDP2. Cells from affected individuals therefore appear to be hypersensitive to topoisomerase II-induced double-strand breaks, and show inhibition of topoisomerase II-dependent gene transcription; among the transcripts affected, many are required for normal neuronal development and maintenance.
Posted by Alina Levtova, MD