Regulation of PARP1/2 and the tankyrases: emerging parallels.
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Embargo End Date
ICR Authors
Authors
Jessop, M
Broadway, BJ
Miller, K
Guettler, S
Broadway, BJ
Miller, K
Guettler, S
Document Type
Journal Article
Date
2024-09-04
Date Accepted
2024-08-06
Abstract
ADP-ribosylation is a prominent and versatile post-translational modification, which regulates a diverse set of cellular processes. Poly-ADP-ribose (PAR) is synthesised by the poly-ADP-ribosyltransferases PARP1, PARP2, tankyrase (TNKS), and tankyrase 2 (TNKS2), all of which are linked to human disease. PARP1/2 inhibitors have entered the clinic to target cancers with deficiencies in DNA damage repair. Conversely, tankyrase inhibitors have continued to face obstacles on their way to clinical use, largely owing to our limited knowledge of their molecular impacts on tankyrase and effector pathways, and linked concerns around their tolerability. Whilst detailed structure-function studies have revealed a comprehensive picture of PARP1/2 regulation, our mechanistic understanding of the tankyrases lags behind, and thereby our appreciation of the molecular consequences of tankyrase inhibition. Despite large differences in their architecture and cellular contexts, recent structure-function work has revealed striking parallels in the regulatory principles that govern these enzymes. This includes low basal activity, activation by intra- or inter-molecular assembly, negative feedback regulation by auto-PARylation, and allosteric communication. Here we compare these poly-ADP-ribosyltransferases and point towards emerging parallels and open questions, whose pursuit will inform future drug development efforts.
Citation
Biochemical Journal, 2024, 481 (17), pp. 1097 - 1123
Source Title
Biochemical Journal
Publisher
PORTLAND PRESS LTD
ISSN
0264-6021
eISSN
1470-8728
Collections
Research Team
Struct Biol Cell Signal