Regulation of PARP1/2 and the tankyrases: emerging parallels DOI Creative Commons
Matthew Jessop,

Benjamin J. Broadway,

Katy Miller

и другие.

Biochemical Journal, Год журнала: 2024, Номер 481(17), С. 1097 - 1123

Опубликована: Авг. 23, 2024

ADP-ribosylation is a prominent and versatile post-translational modification, which regulates diverse set of cellular processes. Poly-ADP-ribose (PAR) synthesised by the poly-ADP-ribosyltransferases PARP1, PARP2, tankyrase (TNKS), 2 (TNKS2), all are linked to human disease. PARP1/2 inhibitors have entered clinic target cancers with deficiencies in DNA damage repair. Conversely, continued face obstacles on their way clinical use, largely owing our limited knowledge molecular impacts effector pathways, concerns around tolerability. Whilst detailed structure-function studies revealed comprehensive picture regulation, mechanistic understanding tankyrases lags behind, thereby appreciation consequences inhibition. Despite large differences architecture contexts, recent work has striking parallels regulatory principles that govern these enzymes. This includes low basal activity, activation intra- or inter-molecular assembly, negative feedback regulation auto-PARylation, allosteric communication. Here we compare point towards emerging open questions, whose pursuit will inform future drug development efforts.

Язык: Английский

Regulation of PARP1/2 and the tankyrases: emerging parallels DOI Creative Commons
Matthew Jessop,

Benjamin J. Broadway,

Katy Miller

и другие.

Biochemical Journal, Год журнала: 2024, Номер 481(17), С. 1097 - 1123

Опубликована: Авг. 23, 2024

ADP-ribosylation is a prominent and versatile post-translational modification, which regulates diverse set of cellular processes. Poly-ADP-ribose (PAR) synthesised by the poly-ADP-ribosyltransferases PARP1, PARP2, tankyrase (TNKS), 2 (TNKS2), all are linked to human disease. PARP1/2 inhibitors have entered clinic target cancers with deficiencies in DNA damage repair. Conversely, continued face obstacles on their way clinical use, largely owing our limited knowledge molecular impacts effector pathways, concerns around tolerability. Whilst detailed structure-function studies revealed comprehensive picture regulation, mechanistic understanding tankyrases lags behind, thereby appreciation consequences inhibition. Despite large differences architecture contexts, recent work has striking parallels regulatory principles that govern these enzymes. This includes low basal activity, activation intra- or inter-molecular assembly, negative feedback regulation auto-PARylation, allosteric communication. Here we compare point towards emerging open questions, whose pursuit will inform future drug development efforts.

Язык: Английский

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