Journal
CHEMICAL SCIENCE
Volume 12, Issue 37, Pages 12468-12475Publisher
ROYAL SOC CHEMISTRY
DOI: 10.1039/d1sc02340c
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Funding
- Chinese Scholarship Council
- DFG (German Research Foundation) [213249687 SFB 1064, 325871075 -SFB 695 1309]
- LMU
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The translation discusses the significance of ADP-ribosylation and the chemical synthesis of linear ADP-ribose oligomers, as well as their affinity for ALC1. The study reveals the length-dependent binding manner of ADPr oligomers to ALC1, illustrating how the activity of this molecular machine is controlled by PAR.
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.
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