Abstract
DNA repair mechanisms such as nucleotide excision repair (NER) and translesion synthesis (TLS) are dependent on proliferating cell nuclear antigen (PCNA), a DNA polymerase accessory protein. Recently, homozygosity for p.Ser228Ile mutation in the PCNA gene was reported in patients with neurodegeneration and impaired NER. Using exome sequencing, we identified a homozygous deleterious mutation, c.648delAG, in the PARP10 gene, in a patient suffering from severe developmental delay. In agreement, PARP10 protein was absent from the patient cells. We have previously shown that PARP10 is recruited by PCNA to DNA damage sites and is required for DNA damage resistance. The patient cells were significantly more sensitive to hydroxyurea and UV-induced DNA damage than control cells, resulting in increased apoptosis, indicating DNA repair impairment in the patient cells. PARP10 deficiency joins the long list of DNA repair defects associated with neurodegenerative disorders, including ataxia telangiectasia, xeroderma pigmentosum, Cockayne syndrome, and the recently reported PCNA mutation.
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Acknowledgments
We would like to thank Drs. Kristin Eckert, Thomas Spratt, and Sergei Grigoryev for materials, support, and advice. This work was supported by the following: NIH 1R01ES026184, Department of Defense CA140303, St. Baldrick Foundation, Concern Foundation, Gittlen Foundation to GLM, and American Cancer Society ACS-IRG-13-043-01 to CMN.
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The study was performed with the approval of the ethical committees of Hadassah Medical Center and the Israeli Ministry of Health.
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Maher Awni Shahrour and Claudia M. Nicolae contributed equally to this work.
An erratum to this article is available at http://dx.doi.org/10.1007/s10048-017-0511-y.
An erratum to this article is available at http://dx.doi.org/10.1007/s10048-016-0503-3.
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Shahrour, M.A., Nicolae, C.M., Edvardson, S. et al. PARP10 deficiency manifests by severe developmental delay and DNA repair defect. Neurogenetics 17, 227–232 (2016). https://doi.org/10.1007/s10048-016-0493-1
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DOI: https://doi.org/10.1007/s10048-016-0493-1