Pathological mutations in PNKP trigger defects in DNA single-strand break repair but not DNA double-strand break repair

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F68378050%3A_____%2F20%3A00540318" target="_blank" >RIV/68378050:_____/20:00540318 - isvavai.cz</a>

Result on the web

<a href="https://academic.oup.com/nar/article/48/12/6672/5854143" target="_blank" >https://academic.oup.com/nar/article/48/12/6672/5854143</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1093/nar/gkaa489" target="_blank" >10.1093/nar/gkaa489</a>

Result language

angličtina

Original language name

Pathological mutations in PNKP trigger defects in DNA single-strand break repair but not DNA double-strand break repair

Original language description

Hereditary mutations in polynucleotide kinase-phosphatase (PNKP) result in a spectrum of neurological pathologies ranging from neurodevelopmental dysfunction in microcephaly with early onset seizures (MCSZ) to neurodegeneration in ataxia oculomotor apraxia-4 (AOA4) and Charcot-Marie-Tooth disease (CMT2B2). Consistent with this, PNKP is implicated in the repair of both DNA single-strand breaks (SSBs) and DNA double-strand breaks (DSBs), lesions that can trigger neurodegeneration and neurodevelopmental dysfunction, respectively. Surprisingly, however, we did not detect a significant defect in DSB repair (DSBR) in primary fibroblasts from PNKP patients spanning the spectrum of PNKP-mutated pathologies. In contrast, the rate of SSB repair (SSBR) is markedly reduced. Moreover, we show that the restoration of SSBR in patient fibroblasts collectively requires both the DNA kinase and DNA phosphatase activities of PNKP, and the fork-head associated (FHA) domain that interacts with the SSBR protein, XRCC1. Notably, however, the two enzymatic activities of PNKP appear to affect different aspects of disease pathology, with reduced DNA phosphatase activity correlating with neurodevelopmental dysfunction and reduced DNA kinase activity correlating with neurodegeneration. In summary, these data implicate reduced rates of SSBR, not DSBR, as the source of both neurodevelopmental and neurodegenerative pathology in PNKP-mutated disease, and the extent and nature of this reduction as the primary determinant of disease severity.

Czech name

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Czech description

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Type

J_ost - Miscellaneous article in a specialist periodical

CEP classification

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OECD FORD branch

10601 - Cell biology

Project

Result was created during the realization of more than one project. More information in the Projects tab.

Continuities

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Publication year

2020

Confidentiality

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Name of the periodical

Nucleic Acids Research

ISSN

1362-4962

e-ISSN

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Volume of the periodical

48

Issue of the periodical within the volume

12

Country of publishing house

GB - UNITED KINGDOM

Number of pages

13

Pages from-to

6672-6684

UT code for WoS article

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EID of the result in the Scopus database

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