ATP-Dependent Chromatin Remodeler CSB Couples DNA Repair Pathways to Transcription with Implications for Cockayne Syndrome and Cancer Therapy DOI Creative Commons
Rabeya Bilkis, Robert J. Lake, Hua-Ying Fan

et al.

Cells, Journal Year: 2025, Volume and Issue: 14(4), P. 239 - 239

Published: Feb. 7, 2025

Efficient DNA lesion repair is crucial for cell survival, especially within actively transcribed regions that contain essential genetic information. Additionally, breaks in of active transcription are prone to generating insertions and deletions, which hallmark features cancer genomes. Cockayne syndrome protein B (CSB) the sole ATP-dependent chromatin remodeler coupling pathways with transcription, leading more efficient transcription. CSB best known its function transcription-coupled nucleotide excision (TC-NER), a process rapidly removes helix-distorting lesions stall RNA polymerase II, such as those created by chemotherapeutic platinum compounds UV irradiation. In addition NER, has also been reported couple homologous recombination Most recently, shown single-strand break this review, we will discuss overlapping distinct mechanisms couples these different We how functions may account emerging roles an innovative target therapy.

Language: Английский

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

Karen Jung,

Karolin Luger

et al.

Proceedings of the National Academy of Sciences, Journal Year: 2022, Volume and Issue: 119(11)

Published: March 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

Language: Английский

Citations

84
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

et al.

Nature Structural & Molecular Biology, Journal Year: 2023, Volume and Issue: 30(5), P. 678 - 691

Published: April 27, 2023

Language: Английский

Citations

45
PARP1: Structural insights and pharmacological targets for inhibition DOI Creative Commons
Jacob O. Spiegel, Bennett Van Houten, Jacob D. Durrant

et al.

DNA repair, Journal Year: 2021, Volume and Issue: 103, P. 103125 - 103125

Published: April 15, 2021

Poly(ADP-ribose) polymerase 1 (PARP1, also known as ADPRT1) is a multifunctional human ADP-ribosyltransferase. It plays role in multiple DNA repair pathways, including the base excision (BER), non-homologous end joining (NHEJ), homologous recombination (HR), and Okazaki-fragment processing pathways. In response to strand breaks, PARP1 covalently attaches ADP-ribose moieties arginine, glutamate, aspartate, cysteine, lysine, serine acceptor sites on both itself other proteins. This signal recruits proteins site of damage. binding these enhances ADP-ribosylation via allosteric communication between distant catalytic domains. this review, we provide general overview emphasize novel potential approaches for pharmacological inhibition. Clinical inhibitors bind pocket, where they directly interfere with ADP-ribosylation. Some may further enhance potency by "trapping" an mechanism, though proposed mode action remains controversial. are used clinically treat some cancers, but resistance common, so urgently needed. One approach be design small molecules that at inter-domain interfaces essential allostery. To illustrate points, review includes instructive videos showing structures mechanisms.

Language: Английский

Citations

63
HPF1 and nucleosomes mediate a dramatic switch in activity of PARP1 from polymerase to hydrolase DOI Creative Commons
Johannes Rudolph,

Genevieve Roberts,

Uma M. Muthurajan

et al.

eLife, Journal Year: 2021, Volume and Issue: 10

Published: March 8, 2021

Poly(ADP-ribose) polymerase 1 (PARP1) is an important player in the response to DNA damage. Recently, Histone PARylation Factor (HPF1) was shown be a critical modulator of activity PARP1 by facilitating histones and redirecting target amino acid specificity from acidic serine residues. Here, we investigate mechanism specific consequences HPF1-mediated using nucleosomes as both activators substrates for PARP1. HPF1 provides that catalytic base Glu284 substantially redirect such become primary recipients PAR chains. Surprisingly, partitions most reaction product free ADP-ribose (ADPR), resulting much shorter chains compared reactions absence HPF1. This switch hydrolase has implications PARP1-mediated damage raises interesting new questions about role intracellular ADPR depletion NAD + .

Language: Английский

Citations

60
HPF1 dynamically controls the PARP1/2 balance between initiating and elongating ADP-ribose modifications DOI Creative Commons
Marie-France Langelier, Ramya Billur, Aleksandr Sverzhinsky

et al.

Nature Communications, Journal Year: 2021, Volume and Issue: 12(1)

Published: Nov. 18, 2021

PARP1 and PARP2 produce poly(ADP-ribose) in response to DNA breaks. HPF1 regulates PARP1/2 catalytic output, most notably permitting serine modification with ADP-ribose. However, is substantially more abundant cells than HPF1, challenging whether can pervasively modulate PARP1. Here, we show biochemically that efficiently output at sub-stoichiometric ratios matching their relative cellular abundances. rapidly associates/dissociates from multiple molecules, initiating before initiates on glutamate/aspartate, accelerating initiation be comparable elongation reactions forming poly(ADP-ribose). This "hit run" mechanism ensures contributions during do not persist interfere PAR chain elongation. We provide structural insights into HPF1/PARP1 assembled a break, assess impact retention DNA. Our data support the prevalence of serine-ADP-ribose efficiency required for an acute damage response.

Language: Английский

Citations

56
PARP1: Liaison of Chromatin Remodeling and Transcription DOI Open Access
Wen Zong,

Yamin Gong,

Wenli Sun

et al.

Cancers, Journal Year: 2022, Volume and Issue: 14(17), P. 4162 - 4162

Published: Aug. 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.

Language: Английский

Citations

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

et al.

Molecular Cell, Journal Year: 2022, Volume and Issue: 82(16), P. 2939 - 2951.e5

Published: July 5, 2022

Language: Английский

Citations

43
A two-step mechanism governing PARP1-DNA retention by PARP inhibitors DOI Creative Commons
Huijun Xue, Amit Bhardwaj, Yandong Yin

et al.

Science Advances, Journal Year: 2022, Volume and Issue: 8(36)

Published: Sept. 7, 2022

PARP inhibitors (PARPi) have emerged as promising cancer therapeutics capable of targeting specific DNA repair pathways, but their mechanism action with respect to PARP1-DNA retention remains unclear. Here, we developed single-molecule assays directly monitor the PARP1 on lesions in real time. Our study reveals a two-step by which PARPi modulate lesions, consisting primary step catalytic inhibition via binding competition NAD + followed an allosteric modulation bound PARPi. While clinically relevant exhibit distinct activities that can either increase or induce its release, potencies are predominantly determined ability outcompete binding. These findings provide mechanistic basis for improved selection according characteristic and enable further development more potent inhibitors.

Language: Английский

Citations

38
Updated protein domain annotation of the PARP protein family sheds new light on biological function DOI Creative Commons
Marcin J. Suskiewicz, Deeksha Munnur, Øyvind Strømland

et al.

Nucleic Acids Research, Journal Year: 2023, Volume and Issue: 51(15), P. 8217 - 8236

Published: June 3, 2023

AlphaFold2 and related computational tools have greatly aided studies of structural biology through their ability to accurately predict protein structures. In the present work, we explored AF2 models 17 canonical members human PARP family supplemented this analysis with new experiments an overview recent published data. proteins are typically involved in modification nucleic acids mono or poly(ADP-ribosyl)ation, but function can be modulated by presence various auxiliary domains. Our provides a comprehensive view structured domains long intrinsically disordered regions within PARPs, offering revised basis for understanding these proteins. Among other functional insights, study model PARP1 domain dynamics DNA-free DNA-bound states enhances connection between ADP-ribosylation RNA ubiquitin-like modifications predicting putative RNA-binding E2-related RWD certain PARPs. line bioinformatic analysis, demonstrate first time PARP14's capability activity vitro. While our insights align existing experimental data probably accurate, they need further validation experiments.

Language: Английский

Citations

35
Clinical PARP inhibitors allosterically induce PARP2 retention on DNA DOI Creative Commons
Marie-France Langelier, Xiaohui Lin, Shan Zha

et al.

Science Advances, Journal Year: 2023, Volume and Issue: 9(12)

Published: March 24, 2023

PARP1 and PARP2 detect DNA breaks, which activates their catalytic production of poly(ADP-ribose) that recruits repair factors contributes to PARP1/2 release from DNA. PARP inhibitors (PARPi) are used in cancer treatment target activity, interfering with increasing persistence on damage. In addition, certain PARPi exert allosteric effects increase retention However, no clinical exhibit this behavior toward PARP1. contrast, we show an effect retains breaks a manner depends communication between the binding regions. Using mutant mimics inhibitor effect, observed increased at cellular damage sites. The AZD5305 also exhibited clear reverse PARP2. Our results can help explain toxicity suggest ways improve moving forward.

Language: Английский

Citations

30