Type

Journal Article

Authors

Keith W Caldecott
Bert B A de Vries
Sherif F El-Khamisy
Gianpiero L Cavalleri
Arjan P M de Brouwer
Felipe Cortés-Ledesma
Norman Delanty
Sean Ennis
Judith Conroy
Elijah Chaila
and 7 others

Subjects

Biochemistry

Topics
transcription factors dna breaks double stranded dna topoisomerase ii alpha physiology base sequence homozygote fluorescent antibody technique animals intellectual disability chromatin immunoprecipitation brain ataxia sequence analysis dna dna binding proteins exome mice abnormalities multiple tdp2 protein human metabolism humans real time polymerase chain reaction seizures nuclear proteins genetics antigens neoplasm neurons dna topoisomerases type ii microarray analysis molecular sequence data transcription genetic

TDP2 protects transcription from abortive topoisomerase activity and is required for normal neural function. (2013)

Abstract Topoisomerase II (TOP2) removes torsional stress from DNA and facilitates gene transcription by introducing transient DNA double-strand breaks (DSBs). Such DSBs are normally rejoined by TOP2 but on occasion can become abortive and remain unsealed. Here we identify homozygous mutations in the TDP2 gene encoding tyrosyl DNA phosphodiesterase-2, an enzyme that repairs 'abortive' TOP2-induced DSBs, in individuals with intellectual disability, seizures and ataxia. We show that cells from affected individuals are hypersensitive to TOP2-induced DSBs and that loss of TDP2 inhibits TOP2-dependent gene transcription in cultured human cells and in mouse post-mitotic neurons following abortive TOP2 activity. Notably, TDP2 is also required for normal levels of many gene transcripts in developing mouse brain, including numerous gene transcripts associated with neurological function and/or disease, and for normal interneuron density in mouse cerebellum. Collectively, these data implicate chromosome breakage by TOP2 as an endogenous threat to gene transcription and to normal neuronal development and maintenance.
Collections Ireland -> Royal College of Surgeons in Ireland -> PubMed

Full list of authors on original publication

Keith W Caldecott, Bert B A de Vries, Sherif F El-Khamisy, Gianpiero L Cavalleri, Arjan P M de Brouwer, Felipe Cortés-Ledesma, Norman Delanty, Sean Ennis, Judith Conroy, Elijah Chaila and 7 others

Experts in our system

1
Gianpiero L Cavalleri
Royal College of Surgeons in Ireland
Total Publications: 35
 
2
Norman Delanty
Royal College of Surgeons in Ireland
Total Publications: 41
 
3
Sean Ennis
University College Dublin
Total Publications: 52
 
4
Judith Conroy
University College Dublin
Total Publications: 24