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DNA repair deficiency and neurological disease

An Erratum to this article was published on 27 January 2009

Key Points

  • DNA repair is crucial for nervous system genesis and function. Mutations in various DNA repair factors can lead to human diseases that are characterized by pronounced neuropathology.

  • Biochemically distinct DNA repair pathways have evolved to repair specific DNA lesions. Requirements for individual DNA repair factors in the nervous system depend on the developmental stage.

  • A main question associated with inherited human DNA repair-deficiency syndromes is the nature, source and tissue-specific outcomes of endogenous DNA damage in the nervous system. Oxidative stress-induced DNA damage is likely to be an important aetiologic agent in these diseases.

  • DNA repair deficiency can lead to different human diseases, typified by microcephaly, reflecting increased cell death during development, or neurodegeneration, from later progressive cellular demise due to accumulated developmental damage or interference with transcription.

  • In some cases, defects in the same DNA repair pathway can result in different neuropathology depending on the particular repair factor targeted or the exact nature of the mutation. For example, defects in nucleotide excision repair can lead to clinically distinct diseases.

  • Because DNA repair deficiency syndromes are congenital, designing drugs to treat these debilitating diseases will require a molecular understanding of the consequences of DNA damage in the developing and mature brain.

Abstract

The ability to respond to genotoxic stress is a prerequisite for the successful development of the nervous system. Mutations in various DNA repair factors can lead to human diseases that are characterized by pronounced neuropathology. In many of these syndromes the neurological component is among the most deleterious aspects of the disease. The nervous system poses a particular challenge in terms of clinical intervention, as the neuropathology associated with these diseases often arises during nervous system development and can be fully penetrant by childhood. Understanding how DNA repair deficiency affects the nervous system will provide a rational basis for therapies targeted at ameliorating the neurological problems in these syndromes.

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Figure 1: DNA damage and repair during nervous system development.
Figure 2: Types of DNA damage and repair.
Figure 3: Repairing DNA strand breaks.
Figure 4: ATM signalling in response to DNA damage.
Figure 5: Nucleotide excision repair and related diseases.

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Acknowledgements

I thank the US National Institutes of Health and the American Lebanese Syrian Associated Charities of St Jude Children's Research Hospital for financial support, and laboratory members for discussions and comments. I also thank an anonymous reviewer for providing helpful suggestions regarding NER diseases. Space constraints limited the number of primary research papers cited.

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DATABASES

OMIM

Alzheimer's disease

AOA1

AOA2

AT

ATLD

LIG4 syndrome

NBS

Parkinson's disease

SCAN1

FURTHER INFORMATION

Information on AT from the Neuromuscular Disease Center at Washington University

Database of allelic variations in XP genes

Database of mutations associated with Werner syndrome

AT children's project

National organization for rare disorders

Bloom's syndrome foundation

Fanconi Anaemia Research Fund

Xeroderma Pigmentosum (XP) Society

Cockayne Syndrome Network

Glossary

Oxidative load

The amount of oxidative stress, in the form of free radicals or reactive oxygen species, that is encountered by a tissue.

Free radical

A molecule that can be produced by metabolism and that contains unstable and reactive unpaired electrons that can damage cellular components such as DNA.

Helical distortion

A topological perturbation of the DNA double helix that the DNA repair machinery can register as damage.

Non-homologous end joining

(NHEJ). One of two distinct biochemical pathways for the repair of DNA DSBs. NHEJ modifies non-compatible termini and directly ligates the broken DNA ends.

Homologous recombination

(HR). One of two distinct biochemical pathways for the repair of DNA DSBs. HR functions in S or G2 of the cell cycle and uses sister chromatid DNA as an undamaged template.

Hypomorphic mutation

A mutation that does not fully eliminate the function of a gene product and that typically results in a less severe phenotype than a loss-of-function mutation.

Cell cycle checkpoint

A biochemical signalling event, activated following stimuli such as DNA damage, that pauses the cell cycle to allow time for recovery from the insult and to maintain cellular homeostasis.

Complementation group

A subgroup of a disease in which the causative defective multiprotein complex can be functionally corrected by reintroducing a missing or defective component from cellular extracts of another individual with the same disease.

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McKinnon, P. DNA repair deficiency and neurological disease. Nat Rev Neurosci 10, 100–112 (2009). https://doi.org/10.1038/nrn2559

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