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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)\u00a0in 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.<\/jats:p>","DOI":"10.1093\/nar\/gkaa489","type":"journal-article","created":{"date-parts":[[2020,6,5]],"date-time":"2020-06-05T11:32:49Z","timestamp":1591356769000},"page":"6672-6684","source":"Crossref","is-referenced-by-count":44,"title":["Pathological mutations in PNKP trigger defects in DNA single-strand break repair but not DNA double-strand break repair"],"prefix":"10.1093","volume":"48","author":[{"given":"Ilona","family":"Kalasova","sequence":"first","affiliation":[{"name":"Department of Genome Dynamics, Institute of Molecular Genetics of the Czech Academy of Sciences, Prague 4, 142 20, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard","family":"Hailstone","sequence":"first","affiliation":[{"name":"Genome Damage and Stability Centre, University of Sussex, Falmer, Brighton BN1 9RQ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Janin","family":"Bublitz","sequence":"first","affiliation":[{"name":"Department of Human Genetics, Hannover Medical School, Hannover, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jovel","family":"Bogantes","sequence":"first","affiliation":[{"name":"Servicio de Cirug\u00eda Reconstructiva, Hospital Rafael \u00c1ngel Calder\u00f3n Guardia, Caja Costarricense de Seguro Social, San Jos\u00e9, Costa Rica"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Winfried","family":"Hofmann","sequence":"first","affiliation":[{"name":"Department of Human Genetics, Hannover Medical School, Hannover, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alejandro","family":"Leal","sequence":"first","affiliation":[{"name":"Section of Genetics and Biotechnology, School of Biology, University of Costa Rica, San Jos\u00e9, Costa Rica"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7235-7269","authenticated-orcid":false,"given":"Hana","family":"Hanzlikova","sequence":"first","affiliation":[{"name":"Department of Genome Dynamics, Institute of Molecular Genetics of the Czech Academy of Sciences, Prague 4, 142 20, Czech Republic"},{"name":"Genome Damage and Stability Centre, University of Sussex, Falmer, Brighton BN1 9RQ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4255-9016","authenticated-orcid":false,"given":"Keith W","family":"Caldecott","sequence":"first","affiliation":[{"name":"Department of Genome Dynamics, Institute of Molecular Genetics of the Czech Academy of Sciences, Prague 4, 142 20, Czech Republic"},{"name":"Genome Damage and Stability Centre, University of Sussex, Falmer, Brighton BN1 9RQ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2020,6,6]]},"reference":[{"key":"2020070614050076200_B1","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1016\/j.yexcr.2014.08.027","article-title":"DNA single-strand break repair","volume":"329","author":"Caldecott","year":"2014","journal-title":"Exp. 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