Chemical synthesis of linear ADP-ribose oligomers up to pentamer and their binding to the oncogenic helicase ALC1. Issue 37 (25th August 2021)

• Record Type: Journal Article
• Authors: Liu, Qiang; Knobloch, Gunnar; Voorneveld, Jim; Meeuwenoord, Nico J.; Overkleeft, Herman S.; van der Marel, Gijsbert A.; Ladurner, Andreas G.; Filippov, Dmitri V.
• Is Part Of: Chemical science. Volume 12:Issue 37(2021)
• Page Start: 12468
• Page End: 12475
• Publication Date: 2021-08-25
• Subjects: Chemistry -- Periodicals; 540.5
• DOI: 10.1039/d1sc02340c
• Languages: English
• ISSNs: 2041-6520

Abstract

Abstract : We report the synthesis of linear ADPr oligomers of defined length up to a pentamer using an improved solid phase method. Binding study with human oncogenic helicase ALC1 shows that ADPr oligomers bind to ALC1 in a length-dependent manner. 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.