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TDP2 keeps the brain healthy

Nature Genetics volume 46, pages 419–421 (2014)Cite this article

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Many inherited human DNA repair deficiency syndromes involve pronounced neurological dysfunction, although the DNA lesions responsible are generally unknown. A new study shows that the phosphodiesterase TDP2 has a key role in protecting the nervous system by preventing DNA breaks induced by aberrant topoisomerase II activity.

Topoisomerases are a unique group of enzymes that relieve torsional stress in DNA by transiently breaking and rejoining DNA strands1,2,3,4. This 'stress relief' is important to allow access to cellular machinery necessary for DNA transactions associated with replication and transcription. Topoisomerases (encompassing seven unique enzymes) are categorized as either type I or type II, depending on whether a transient single-strand break or a double-strand break (DSB), respectively, is introduced into DNA2,3. Strand scission involves the generation of a reversible phosphodiester linkage between the active site tyrosine of topoisomerase and the sugar moiety of DNA2,3,5. However, severing DNA strands comes with a risk—if topoisomerase function is perturbed during this process, the enzyme can undergo an abortive reaction whereby the topoisomerase becomes trapped on the DNA. In this scenario, DNA breaks persist and must be resolved to avoid accumulation of DNA damage. The resolution of these breaks often involves a tyrosyl-DNA phosphodiesterase, an enzyme that is required to release DNA from a trapped topoisomerase2,3. Failure of this enzymatic activity will contribute to DNA damage that can affect cellular function. On page 419 of this issue, Keith Caldecott and colleagues show that inactivation of tyrosyl-DNA phosphodiesterase-2 (TDP2), an enzyme that specifically cleaves the linkage between topoisomerase II (TOP2) and DNA, is associated with neurological disease characterized by cognitive defects, seizures and ataxia6.

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Figure 1: TDP2 protects the brain by repairing DNA damage from abortive TOP2 activity.

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  1. Peter J. McKinnon is in the Department of Genetics, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.,

    Peter J McKinnon

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  1. Peter J McKinnon
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Correspondence to Peter J McKinnon.

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McKinnon, P. TDP2 keeps the brain healthy. Nat Genet 46, 419–421 (2014). https://doi.org/10.1038/ng.2967

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