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PARP1 catalytic variants reveal branching and chain length-specific functions of poly(ADP-ribose) in cellular physiology and stress response

Aberle, Lisa; Krüger, Annika; Reber, Julia M; Lippmann, Michelle; Hufnagel, Matthias; Schmalz, Michael; Trussina, Irmela R E A; Schlesiger, Sarah; Zubel, Tabea; Schütz, Karina; Marx, Andreas; Hartwig, Andrea; Ferrando-May, Elisa; Bürkle, Alexander; Mangerich, Aswin

Abstract:
Poly(ADP-ribosyl)ation regulates numerous cellular processes like genome maintenance and cell death, thus providing protective functions but also contributing to several pathological conditions. Poly(ADP-ribose) (PAR) molecules exhibit a remarkable heterogeneity in chain lengths and branching frequencies, but the biological significance of this is basically unknown. To unravel structure-specific functions of PAR, we used PARP1 mutants producing PAR of different qualities, i.e. short and hypobranched (PARP1\G972R), short and moderately hyperbranched (PARP1\Y986S), or strongly hyperbranched PAR (PARP1\Y986H). By reconstituting HeLa PARP1 knockout cells, we demonstrate that PARP1\G972R negatively affects cellular endpoints, such as viability, cell cycle progression and genotoxic stress resistance. In contrast, PARP1\Y986S elicits only mild effects, suggesting that PAR branching compensates for short polymer length. Interestingly, PARP1\Y986H exhibits moderate beneficial effects on cell physiology. Furthermore, different PARP1 mutants have distinct effects on molecular processes, such as gene expression and protein localization dynamics of PARP1 itself, and of its downstream factor XRCC1. ... mehr

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Verlagsausgabe §
DOI: 10.5445/IR/1000129912
Veröffentlicht am 19.02.2021
Originalveröffentlichung
DOI: 10.1093/nar/gkaa590
Scopus
Zitationen: 1
Web of Science
Zitationen: 1
Dimensions
Zitationen: 2
Cover der Publikation
Zugehörige Institution(en) am KIT Institut für Angewandte Biowissenschaften (IAB)
Publikationstyp Zeitschriftenaufsatz
Publikationsmonat/-jahr 10.2020
Sprache Englisch
Identifikator ISSN: 0305-1048, 1362-4962
KITopen-ID: 1000129912
Erschienen in Nucleic acids research
Verlag Oxford University Press (OUP)
Band 48
Heft 18
Seiten 10015–10033
Vorab online veröffentlicht am 15.07.2020
Nachgewiesen in Scopus
Web of Science
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