A unified mechanism for PARP inhibitor-induced PARP1 chromatin retention at DNA damage sites in living cells DOI Creative Commons
Petar-Bogomil Kanev,

Sylvia Varhoshkova,

Irina Georgieva

и другие.

Cell Reports, Год журнала: 2024, Номер 43(5), С. 114234 - 114234

Опубликована: Май 1, 2024

Poly(ADP-ribose) polymerase (PARP) inhibitors (PARPis) not only suppress PARP1 catalytic activity but also prolong its association to damaged chromatin. Here, through live-cell imaging, we quantify the alterations in dynamics and elicited by seven PARPis over a wide range of concentrations deliver unified mechanism PARPi-induced chromatin retention. We find that gross retention at DNA damage sites is jointly governed inhibition allosteric trapping, albeit strictly independent manner—catalytic causes multiple unproductive binding-dissociation cycles PARP1, while trapping prolongs lesion-bound state greatly increase overall Importantly, stronger produces greater temporal shifts downstream repair events superior cytotoxicity, highlighting retention, complex precisely quantifiable characteristic PARPis, as valuable biomarker for PARPi efficacy. Our approach can be promptly repurposed interrogating properties DNA-repair-targeting compounds beyond PARPis.

Язык: Английский

The mechanisms of integral membrane protein biogenesis DOI
Ramanujan S. Hegde, Robert J. Keenan

Nature Reviews Molecular Cell Biology, Год журнала: 2021, Номер 23(2), С. 107 - 124

Опубликована: Сен. 23, 2021

Язык: Английский

Процитировано

158
The expanding universe of PARP1-mediated molecular and therapeutic mechanisms DOI Creative Commons
Dan Huang, W. Lee Kraus

Molecular Cell, Год журнала: 2022, Номер 82(12), С. 2315 - 2334

Опубликована: Март 9, 2022

Язык: Английский

Процитировано

158
ADP-ribosylation from molecular mechanisms to therapeutic implications DOI Creative Commons
Marcin J. Suskiewicz, Evgeniia Prokhorova, J.G.M. Rack

и другие.

Cell, Год журнала: 2023, Номер 186(21), С. 4475 - 4495

Опубликована: Окт. 1, 2023

ADP-ribosylation is a ubiquitous modification of biomolecules, including proteins and nucleic acids, that regulates various cellular functions in all kingdoms life. The recent emergence new technologies to study has reshaped our understanding the molecular mechanisms govern establishment, removal, recognition this modification, as well its impact on organismal function. These advances have also revealed intricate involvement human physiology pathology enormous potential their manipulation holds for therapy. In review, we present state-of-the-art findings covering work structural biology, biochemistry, cell clinical aspects ADP-ribosylation.

Язык: Английский

Процитировано

70
Transcription–replication conflicts underlie sensitivity to PARP inhibitors DOI Creative Commons
Michalis Petropoulos,

Angeliki Karamichali,

Giacomo G. Rossetti

и другие.

Nature, Год журнала: 2024, Номер 628(8007), С. 433 - 441

Опубликована: Март 20, 2024

Abstract An important advance in cancer therapy has been the development of poly(ADP-ribose) polymerase (PARP) inhibitors for treatment homologous recombination (HR)-deficient cancers 1–6 . PARP trap PARPs on DNA. The trapped are thought to block replisome progression, leading formation DNA double-strand breaks that require HR repair 7 Here we show PARP1 functions together with TIMELESS and TIPIN protect early S phase from transcription–replication conflicts. Furthermore, synthetic lethality deficiency is due an inability damage caused by conflicts, rather than PARPs. Along these lines, inhibiting transcription elongation rendered HR-deficient cells resistant depleting small-interfering RNA was lethal deficiency. Thus, enzymatic activity may suffice efficacy settings.

Язык: Английский

Процитировано

56
PARP1 associates with R-loops to promote their resolution and genome stability DOI Creative Commons

Natalie Laspata,

Parminder Kaur, Sofiane Y. Mersaoui

и другие.

Nucleic Acids Research, Год журнала: 2023, Номер 51(5), С. 2215 - 2237

Опубликована: Фев. 16, 2023

Abstract PARP1 is a DNA-dependent ADP-Ribose transferase with ADP-ribosylation activity that triggered by DNA breaks and non-B structures to mediate their resolution. was also recently identified as component of the R-loop-associated protein-protein interaction network, suggesting potential role for in resolving this structure. R-loops are three-stranded nucleic acid consist RNA–DNA hybrid displaced non-template strand. involved crucial physiological processes but can be source genome instability if persistently unresolved. In study, we demonstrate binds vitro associates R-loop formation sites cells which activates its activity. Conversely, inhibition or genetic depletion causes an accumulation unresolved promotes genomic instability. Our study reveals novel sensor highlights suppressor

Язык: Английский

Процитировано

50
PARP14 and PARP9/DTX3L regulate interferon-induced ADP-ribosylation DOI

Pulak Kar,

Chatrin Chatrin, N Mimica Dukic

и другие.

The EMBO Journal, Год журнала: 2024, Номер 43(14), С. 2929 - 2953

Опубликована: Июнь 4, 2024

Язык: Английский

Процитировано

16
Ubiquitin is directly linked via an ester to protein-conjugated mono-ADP-ribose DOI Creative Commons
Daniel S. Bejan,

Rachel E. Lacoursiere,

Jonathan N. Pruneda

и другие.

The EMBO Journal, Год журнала: 2025, Номер unknown

Опубликована: Фев. 25, 2025

Abstract The prevailing view on post-translational modifications (PTMs) is that a single amino acid modified with PTM at any given time. However, recent work has demonstrated crosstalk between different PTMs, some occurring the same residue. Such interplay seen ADP-ribosylation and ubiquitylation. For example, DELTEX E3 ligases were reported to ubiquitylate hydroxyl group free NAD + ADP-ribose in vitro, generating noncanonical ubiquitin ester-linked species. In this report, we show, for first time, dual occurs cells mono-ADP-ribosylated (MARylated) PARP10 Glu/Asp sites form MAR ester. We call process mono-ADP-ribosyl ubiquitylation or MARUbylation. Using chemical enzymatic treatments, including newly characterized bacterial deubiquitinase esterase-specific activity, discovered multiple PARPs are MARUbylated extended K11-linked polyubiquitin chains when exogenously expressed. Finally, show response type I interferon stimulation, MARUbylation can occur endogenously PARP targets. Thus, represents new broadens our understanding of function PARP-mediated cells.

Язык: Английский

Процитировано

2
PARPs in lipid metabolism and related diseases DOI Creative Commons
Magdolna Szántó,

Rebecca Gupte,

W. Lee Kraus

и другие.

Progress in Lipid Research, Год журнала: 2021, Номер 84, С. 101117 - 101117

Опубликована: Авг. 25, 2021

PARPs and tankyrases (TNKS) represent a family of 17 proteins. were originally identified as DNA repair factors, nevertheless, recent advances have shed light on their role in lipid metabolism. To date, PARP1, PARP2, PARP3, tankyrases, PARP9, PARP10, PARP14 reported to multi-pronged connections The activity PARP enzymes is fine-tuned by set cholesterol-based compounds oxidized cholesterol derivatives, steroid hormones or bile acids. In turn, modulate several key processes homeostasis (lipotoxicity, fatty acid biosynthesis, lipoprotein homeostasis, oxidation, etc.). are also cofactors lipid-responsive nuclear receptors transcription factors through which regulate metabolism homeostasis. activation often represents disruptive signal (lipid) metabolism, PARP-dependent changes pathophysiological the development hyperlipidemia, obesity, alcoholic non-alcoholic liver disease, type II diabetes its complications, atherosclerosis, cardiovascular aging skin pathologies, just name few. this synopsis we will review evidence supporting beneficial effects pharmacological inhibitors these diseases/pathologies propose repurposing already available for treatment various malignancies.

Язык: Английский

Процитировано

101
PARP1: Liaison of Chromatin Remodeling and Transcription DOI Open Access
Wen Zong,

Yamin Gong,

Wenli Sun

и другие.

Cancers, Год журнала: 2022, Номер 14(17), С. 4162 - 4162

Опубликована: Авг. 27, 2022

Poly(ADP-ribosyl)ation (PARylation) is a covalent post-translational modification and plays key role in the immediate response of cells to stress signals. Poly(ADP-ribose) polymerase 1 (PARP1), founding member PARP superfamily, synthesizes long branched polymers ADP-ribose (PAR) onto acceptor proteins, thereby modulating their function local surrounding. PARP1 most prominent PARPs responsible for production about 90% PAR cell. Therefore, PARylation play pleotropic wide range cellular processes, such as DNA repair genomic stability, cell death, chromatin remodeling, inflammatory gene transcription. has DNA-binding catalytic activities that are important repair, yet also modulate conformation transcription, which can be independent damage response. homeostasis have been implicated multiple diseases, including inflammation, stroke, diabetes cancer. Studies molecular action biological provide basis development pharmaceutic strategies clinical applications. This review focuses primarily on regulation remodeling transcriptional activation.

Язык: Английский

Процитировано

48
Captured snapshots of PARP1 in the active state reveal the mechanics of PARP1 allostery DOI Creative Commons

Élise Rouleau-Turcotte,

Dragomir B. Krastev, Stephen J. Pettitt

и другие.

Molecular Cell, Год журнала: 2022, Номер 82(16), С. 2939 - 2951.e5

Опубликована: Июль 5, 2022

Язык: Английский

Процитировано

43