Chemical synthesis of linear ADP-ribose oligomers up to pentamer and their binding to the oncogenic helicase ALC1

Liu, Qiang; Knobloch, Gunnar; Voorneveld, Jim; Meeuwenoord, Nico J.; Overkleeft, Herman S.; Marel, Gijsbert A. van der; Ladurner, Andreas G. und Filippov, Dmitri V. (2021): Chemical synthesis of linear ADP-ribose oligomers up to pentamer and their binding to the oncogenic helicase ALC1. In: Chemical Science, Bd. 12, Nr. 37: S. 12468-12475

Abstract

ADP-ribosylation is a pivotal post-translational modification that mediates various important cellular processes producing negatively charged biopolymer, poly (ADP-ribose), the functions of which need further elucidation. Toward this end, the availability of well-defined ADP-ribose (ADPr) oligomers in sufficient quantities is a necessity. In this work, we demonstrate the chemical synthesis of linear ADPr oligomers of defined, increasing length using a modified solid phase synthesis method. An advanced phosphoramidite building block temporarily protected with the base sensitive Fm-group was designed and implemented in the repeating pyrophosphate formation via a P(v)-P(iii) coupling procedure on Tentagel solid support. Linear ADPr oligomers up to a pentamer were successfully synthesized and their affinity for the poly-(ADP-ribose)-binding macrodomain of the human oncogenic helicase and chromatin remodeling enzyme ALC1 was determined. Our data reveal a length-dependent binding manner of the nucleic acid, with larger ADPr oligomers exhibiting higher binding enthalpies for ALC1, illustrating how the activity of this molecular machine is gated by PAR.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• ISSN: 2041-6520
• Sprache: Englisch