Slow Dissociation from the PARP1–HPF1 Complex Drives Inhibitor Potency DOI Creative Commons
Petra Stojanovic, Karolin Luger, Johannes Rudolph

и другие.

Biochemistry, Год журнала: 2023, Номер 62(16), С. 2382 - 2390

Опубликована: Авг. 2, 2023

PARP1, upon binding to damaged DNA, is activated perform poly ADP-ribosylation (PARylation) on itself and other proteins, which leads relaxation of chromatin recruitment DNA repair factors. HPF1 was recently discovered as a protein cofactor PARP1 that directs preferential PARylation histones over targets by contributing altering the active site. Inhibitors (PARPi) are used in treatment BRCA–/– cancers, but basis for their potency cells, especially context HPF1, not fully understood. Here, we demonstrate simple one-step association eight different PARPi with measured rates (kon) 0.8–6 μM–1 s–1. We find only minor differences these when comparing PARP1–HPF1 complex. By characterizing dissociation (koff) constants (KD) two more PARPi, find, example, saruparib has half-life 22.5 h fluzoparib higher affinity presence just like structurally related compound olaparib. using KD kon calculate koff, cells correlates best koff from Our data suggest drug complex should be parameter choice guiding development next-generation PARPi.

Язык: Английский

Inhibitors of PARP: Number crunching and structure gazing DOI Creative Commons
Johannes Rudolph,

Karen Jung,

Karolin Luger

и другие.

Proceedings of the National Academy of Sciences, Год журнала: 2022, Номер 119(11)

Опубликована: Март 8, 2022

SignificancePARP is an important target in the treatment of cancers, particularly patients with breast, ovarian, or prostate cancer that have compromised homologous recombination repair (i.e., BRCA

Язык: Английский

Процитировано

84
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
HPF1-dependent histone ADP-ribosylation triggers chromatin relaxation to promote the recruitment of repair factors at sites of DNA damage DOI
Rebecca Smith, Siham Zentout,

Magdalena B. Rother

и другие.

Nature Structural & Molecular Biology, Год журнала: 2023, Номер 30(5), С. 678 - 691

Опубликована: Апрель 27, 2023

Язык: Английский

Процитировано

45
Poly(ADP-ribosyl)ation enhances nucleosome dynamics and organizes DNA damage repair components within biomolecular condensates DOI Creative Commons
Michael L. Nosella, Tae Hun Kim, Shuya Kate Huang

и другие.

Molecular Cell, Год журнала: 2024, Номер 84(3), С. 429 - 446.e17

Опубликована: Янв. 11, 2024

Язык: Английский

Процитировано

19
The regulatory landscape of the human HPF1- and ARH3-dependent ADP-ribosylome DOI Creative Commons
Ivo A. Hendriks, Sara C. Buch-Larsen, Evgeniia Prokhorova

и другие.

Nature Communications, Год журнала: 2021, Номер 12(1)

Опубликована: Окт. 8, 2021

Abstract Despite the involvement of Poly(ADP-ribose) polymerase-1 (PARP1) in many important biological pathways, target residues PARP1-mediated ADP-ribosylation remain ambiguous. To explicate regulome, we analyze human cells depleted for key regulators PARP1 activity, histone PARylation factor 1 (HPF1) and ADP-ribosylhydrolase 3 (ARH3). Using quantitative proteomics, characterize 1,596 sites, displaying up to 1000-fold regulation across investigated knockout cells. We find that HPF1 ARH3 inversely homogenously regulate serine ADP-ribosylome on a proteome-wide scale with consistent adherence lysine-serine-motifs, suggesting targeting is independent ARH3. Notably, do not detect an HPF1-dependent residue switch from glutamate/aspartate under conditions. Our data support notion mainly exists as mono-ADP-ribosylation cells, reveal remarkable degree co-modification other post-translational modifications.

Язык: Английский

Процитировано

80
Serine-linked PARP1 auto-modification controls PARP inhibitor response DOI Creative Commons
Evgeniia Prokhorova,

Florian Zobel,

Rebecca Smith

и другие.

Nature Communications, Год журнала: 2021, Номер 12(1)

Опубликована: Июль 1, 2021

Abstract Poly(ADP-ribose) polymerase 1 (PARP1) and PARP2 are recruited activated by DNA damage, resulting in ADP-ribosylation at numerous sites, both within PARP1 itself other proteins. Several inhibitors currently employed the clinic or undergoing trials for treatment of various cancers. These drugs act primarily trapping on damaged chromatin, which can lead to cell death, especially cells with repair defects. Although is thought be caused catalytic inhibition PARP-dependent modification, implying that (ADPr) counteract trapping, it not known exact sites important this process. Following recent findings PARP1- PARP2-mediated modification predominantly serine-linked, we demonstrate here serine ADPr plays a vital role cellular responses PARP1/PARP2 inhibitors. Specifically, identify three residues (499, 507, 519) as key whose efficient HPF1-dependent counters contributes inhibitor tolerance. Our data implicate genes encode serine-specific regulators, HPF1 ARH3, potential therapy biomarkers.

Язык: Английский

Процитировано

76
The BRCT domain of PARP1 binds intact DNA and mediates intrastrand transfer DOI Creative Commons
Johannes Rudolph, Uma M. Muthurajan, Megan Palacio

и другие.

Molecular Cell, Год журнала: 2021, Номер 81(24), С. 4994 - 5006.e5

Опубликована: Дек. 1, 2021

Язык: Английский

Процитировано

72
PARP inhibitors trap PARP2 and alter the mode of recruitment of PARP2 at DNA damage sites DOI Creative Commons
Xiaohui Lin, Wenxia Jiang, Johannes Rudolph

и другие.

Nucleic Acids Research, Год журнала: 2022, Номер 50(7), С. 3958 - 3973

Опубликована: Март 23, 2022

Dual-inhibitors of PARP1 and PARP2 are promising anti-cancer drugs. In addition to blocking PARP1&2 enzymatic activity, PARP inhibitors also extend the lifetime DNA damage-induced foci, termed trapping. Trapping is important for therapeutic effects inhibitors. Using live-cell imaging, we found that cause persistent foci by switching mode recruitment from a predominantly PARP1- PAR-dependent rapid exchange WGR domain-mediated stalling on DNA. Specifically, PARP1-deletion markedly reduces but does not abolish foci. The residual in PARP1-deficient cells DNA-dependent abrogated R140A mutation domain. Yet, PARP2-R140A forms normal PARP1-proficient cells. cells, - niraparib, talazoparib, and, lesser extent, olaparib enhance preventing exchange. This trapping independent auto-PARylation abolished domain H415A catalytic Taken together, trap physically via WGR-DNA interaction while suppressing PARP2.

Язык: Английский

Процитировано

41
PARPs and ADP-ribosylation: Deciphering the complexity with molecular tools DOI Creative Commons
Morgan Dasovich, Anthony K. L. Leung

Molecular Cell, Год журнала: 2023, Номер 83(10), С. 1552 - 1572

Опубликована: Апрель 28, 2023

Язык: Английский

Процитировано

34
The logic of protein post‐translational modifications (PTMs): Chemistry, mechanisms and evolution of protein regulation through covalent attachments DOI Creative Commons
Marcin J. Suskiewicz

BioEssays, Год журнала: 2024, Номер 46(3)

Опубликована: Янв. 21, 2024

Abstract Protein post‐translational modifications (PTMs) play a crucial role in all cellular functions by regulating protein activity, interactions and half‐life. Despite the enormous diversity of modifications, various PTM systems show parallels their chemical catalytic underpinnings. Here, focussing on that involve addition new elements to amino‐acid sidechains, I describe historical milestones fundamental concepts support current understanding PTMs. The survey covers selected key research programmes, including study phosphorylation as regulatory switch, ubiquitylation degradation signal histone functional code. contribution techniques for studying PTMs is also discussed. central part essay explores shared principles strategies observed across diverse systems, together with mechanisms substrate selection, reversibility erasers recognition reader domains. Similarities basic mechanism are highlighted implications final dedicated evolutionary trajectories beginning possible emergence context rivalry prokaryotic world. Together, provides unified perspective world major modifications.

Язык: Английский

Процитировано

9