TDP2 protects transcription from abortive topoisomerase activity and is required for normal neural function

Area of Science:

• Genetics
• Neuroscience
• Molecular Biology

Background:

• Topoisomerase II (TOP2) is crucial for DNA management, introducing transient double-strand breaks (DSBs) for transcription.
• TOP2-induced DSBs can become persistent if not properly repaired, potentially leading to cellular dysfunction.

Purpose of the Study:

• To investigate the genetic basis of intellectual disability, seizures, and ataxia associated with unrepaired TOP2-induced DSBs.
• To elucidate the role of tyrosyl DNA phosphodiesterase-2 (TDP2) in repairing these specific DNA lesions and its impact on neuronal health.

Main Methods:

• Genetic analysis to identify mutations in affected individuals.
• Cellular assays to assess DNA repair capacity and sensitivity to TOP2-induced DSBs.
• Analysis of gene transcription and neuronal development in cellular and mouse models.

Main Results:

• Homozygous mutations in the TDP2 gene were identified in individuals with intellectual disability, seizures, and ataxia.
• TDP2-deficient cells exhibit hypersensitivity to TOP2-induced DSBs and impaired TOP2-dependent transcription.
• Loss of TDP2 affects gene expression in the developing mouse brain and interneuron density in the cerebellum.

Conclusions:

• Persistent TOP2-induced DNA breaks are detrimental to gene transcription and neuronal development.
• TDP2 is essential for repairing abortive TOP2-induced DSBs, maintaining genomic integrity, and supporting normal neurological function.
• This study highlights a novel mechanism linking DNA repair defects to neurodevelopmental disorders.