Research Papers:

Splice variants of the endonucleases XPF and XPG contain residual DNA repair capabilities and could be a valuable tool for personalized medicine

Janin Lehmann, Steffen Schubert, Christina Seebode, Antje Apel, Andreas Ohlenbusch and Steffen Emmert _

PDF  |  HTML  |  How to cite

Oncotarget. 2018; 9:1012-1027. https://doi.org/10.18632/oncotarget.23105

Metrics: PDF 1376 views  |   HTML 2486 views  |   ?  


Janin Lehmann1, Steffen Schubert2, Christina Seebode1, Antje Apel3, Andreas Ohlenbusch4 and Steffen Emmert1,3

1Clinic and Policlinic for Dermatology and Venereology, University Medical Center Rostock, Rostock, Germany

2Information Network of Departments of Dermatology (IVDK), University Medical Center Goettingen, Goettingen, Germany

3Department of Dermatology, Venereology and Allergology, University Medical Center Goettingen, Goettingen, Germany

4Department of Pediatrics and Adolescent Medicine, Division of Pediatric Neurology, University Medical Center Goettingen, Goettingen, Germany

Correspondence to:

Steffen Emmert, email: [email protected]

Keywords: xeroderma pigmentosum; nucleotide excision repair; interstrand crosslink repair; spontaneous mRNA splice variants

Received: September 19, 2017     Accepted: November 15, 2017     Published: December 08, 2017


The two endonucleases XPF and XPG are essentially involved in nucleotide excision repair (NER) and interstrand crosslink (ICL) repair. Defects in these two proteins result in severe diseases like xeroderma pigmentosum (XP). We applied our newly CRISPR/Cas9 generated human XPF knockout cell line with complete loss of XPF and primary fibroblasts from an XP-G patient (XP20BE) to analyze until now uncharacterized spontaneous mRNA splice variants of these two endonucleases. Functional analyses of these variants were performed using luciferase-based reporter gene assays. Two XPF and XPG splice variants with residual repair capabilities in NER, as well as ICL repair could be identified. Almost all variants are severely C-terminally truncated and lack important protein-protein interaction domains. Interestingly, XPF-202, differing to XPF-003 in the first 12 amino acids only, had no repair capability at all, suggesting an important role of this region during DNA repair, potentially concerning protein-protein interaction. We also identified splice variants of XPF and XPG exerting inhibitory effects on NER. Moreover, we showed that the XPF and XPG splice variants presented with different inter-individual expression patterns in healthy donors, as well as in various tissues. With regard to their residual repair capability and dominant-negative effects, functionally relevant spontaneous XPF and XPG splice variants present promising prognostic marker candidates for individual cancer risk, disease outcome, or therapeutic success. This merits further investigations, large association studies, and translational research within clinical trials in the future.

Creative Commons License All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 4.0 License.
PII: 23105