Poly(ADP-ribose)-mediated interplay of XPA and PARP1 leads to reciprocal regulation of protein function

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SFB 969 TP B04: Regulation der Proteinfunktion durch Poly(ADP-Ribose)
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FEBS Journal. 2014, 281(16), pp. 3625-3641. ISSN 1742-464X. eISSN 1742-4658. Available under: doi: 10.1111/febs.12885
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Poly(ADP-ribose) (PAR) is a complex and reversible post-translational modification that controls protein function and localization through covalent modification of, or noncovalent binding to target proteins. Previously, we and others characterized the noncovalent, high-affinity binding of the key nucleotide excision repair (NER) protein XPA to PAR. In the present study, we address the functional relevance of this interaction. First, we confirm that pharmacological inhibition of cellular poly(ADP-ribosyl)ation (PARylation) impairs NER efficacy. Second, we demonstrate that the XPA–PAR interaction is mediated by specific basic amino acids within a highly conserved PAR-binding motif, which overlaps the DNA damage-binding protein 2 (DDB2) and transcription factor II H (TFIIH) interaction domains of XPA. Third, biochemical studies reveal a mutual regulation of PARP1 and XPA functions showing that, on the one hand, the XPA–PAR interaction lowers the DNA binding affinity of XPA, whereas, on the other hand, XPA itself strongly stimulates PARP1 enzymatic activity. Fourth, microirradiation experiments in U2OS cells demonstrate that PARP inhibition alters the recruitment properties of XPA-green fluorescent protein to sites of laser-induced DNA damage. In conclusion, our results reveal that XPA and PARP1 regulate each other in a reciprocal and PAR-dependent manner, potentially acting as a fine-tuning mechanism for the spatio-temporal regulation of the two factors during NER.

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ISO 690FISCHER, Jan M.F., Oliver POPP, Daniel GEBHARD, Sebastian VEITH, Arthur FISCHBACH, Sascha BENEKE, Alfred LEITENSTORFER, Jörg BERGEMANN, Martin SCHEFFNER, Elisa FERRANDO-MAY, Aswin MANGERICH, Alexander BÜRKLE, 2014. Poly(ADP-ribose)-mediated interplay of XPA and PARP1 leads to reciprocal regulation of protein function. In: FEBS Journal. 2014, 281(16), pp. 3625-3641. ISSN 1742-464X. eISSN 1742-4658. Available under: doi: 10.1111/febs.12885
BibTex
@article{Fischer2014-08PolyA-28491,
  year={2014},
  doi={10.1111/febs.12885},
  title={Poly(ADP-ribose)-mediated interplay of XPA and PARP1 leads to reciprocal regulation of protein function},
  number={16},
  volume={281},
  issn={1742-464X},
  journal={FEBS Journal},
  pages={3625--3641},
  author={Fischer, Jan M.F. and Popp, Oliver and Gebhard, Daniel and Veith, Sebastian and Fischbach, Arthur and Beneke, Sascha and Leitenstorfer, Alfred and Bergemann, Jörg and Scheffner, Martin and Ferrando-May, Elisa and Mangerich, Aswin and Bürkle, Alexander}
}
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