Deciphering the dark side of histone ADP-ribosylation: what structural features of damaged nucleosome regulate the activities of PARP1 and PARP2

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown

Опубликована: Янв. 30, 2025

ABSTRACT Poly(ADP-ribose) polymerases are critical enzymes contributing to regulation of numerous cellular processes, including DNA repair. Within the PARP family, PARP1 and PARP2 primarily facilitate PARylation in nucleus, particularly responding genotoxic stress. The activity PARPs is influenced by nature damage multiple protein partners, with HPF1 being important one. Forming a joint active site (PARP2), contributes histone following chromatin remodelling during stress events. This study elucidates interrelation between presence location one-nucleotide gap within nucleosome core particle (NCP) activities automodification heteromodification histones. Utilizing combination classical biochemical methods fluorescence-based technique single-molecule mass photometry approach, we have shown that NCP architecture impacts efficiency pattern ADP-ribosylation binding histones-associated damaged more significantly for than PARP1. Analysis based on existing studies HPF1-dependent ADP-ribosylome structural dynamics allows suggest conformational flexibility tails modulated post-translational modifications crucial delineating distinct roles responses. GRAPHICAL

Язык: Английский

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The clinically applied PARP inhibitor talazoparib ameliorates imiquimod-induced psoriasis in mice without reducing skin inflammation

Frontiers in Pharmacology, Год журнала: 2025, Номер 16

Опубликована: Фев. 19, 2025

Considering the role PARPs play in inflammation, we assessed effect of PARP inhibition an inflammatory skin condition, psoriasis, to explore novel avenues for potential repurposing inhibitors that are currently used tumour therapy. The imiquimod (IMQ)-induced model psoriasis was applied BALB/c mice. Mice received daily intraperitoneal injection either one four or their vehicle prior treatment shaved back mice with IMQ-containing cream control days. appearance scored according extent erythema, induration and scaling. most effective inhibitor selected detailed studies on mouse a human keratinocyte cell line. Of inhibitors, talazoparib rucaparib improved imiquimod-induced symptoms skin. Application resulted maintained terminal differentiation reduced proliferation epidermal keratinocytes. Conversely, also enhanced production pro-inflammatory chemokines These effects associated increased mitochondrial reactive oxygen species consequent activation pro-apoptotic pathways by promotes keratinocytes may be beneficial psoriasis. Despite fact exerted skin, which is not unprecedented anti-psoriatic therapy, these findings advance conduction pre-clinical clinical trials management.

Язык: Английский

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HPF1 Regulates Pol β Efficiency in Nucleosomes via the Modulation of Total Poly(ADP-Ribose) Synthesis

International Journal of Molecular Sciences, Год журнала: 2025, Номер 26(5), С. 1794 - 1794

Опубликована: Фев. 20, 2025

The maintenance of genome stability and the prevention genotoxic damage to DNA require immediate repair. In cell, repair process is usually preceded by a release from complexes with chromatin proteins accompanied nucleosome sliding, relaxing or disassembly. Base excision (BER) corrects most common lesions, which does not disturb helix dramatically. Notably, small lesions can be repaired in without global decompaction. One regulatory mechanisms poly(ADP-ribosyl)ation, leading relaxation nucleosome. our work, we demonstrated that recently discovered protein, HPF1, modulate efficiency one key BER stages-DNA synthesis-via regulation total poly(ADP-ribosyl)ation. Accordingly, investigated both short-patch long-patch synthesis catalyzed polymerase β (pol β; main BER) showed HPF1's influence on poly(ADP-ribosyl)ation PARP1 especially PARP2 results more efficient case pathway nucleosomes. Additionally, HPF1-dependent was found positively regulate BER.

Язык: Английский

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Deciphering the molecular transcriptomic mechanisms of carbon ion beams and X-ray on rice seedlings

BMC Genomics, Год журнала: 2025, Номер 26(1)

Опубликована: Март 28, 2025

Ionizing radiation (IR) is an abiotic stress factor that can be not only a means to explore plant resistance but also potent mutagen in agricultural breeding. The diverse physical parameters of different types IR result varying effects on plants, which turn leads differences the spectrum genetic variations offspring. Investigating response mechanisms crucial for enhancing and comprehending mutation generation from various mutagenic sources Nevertheless, mechanism underlying complex responses plants are yet fully comprehended. we conducted transcriptome sequencing rice seedlings exhibited relative root length approximately 69% after being exposed carbon ion beams (CIBs) X-ray respectively. results revealed induced greater number differentially expressed genes (DEGs) than CIBs, with 5681 2198 DEGs were identified Gene Ontology (GO) Kyoto Encyclopedia Genes Genomes (KEGG) analyses indicated DNA replication, damage repair, phytohormone signaling, antioxidant pathways implicated seedling IR. These demonstrated patterns following Additionally, through two linear energy transfer (LET), found some common contribute seedlings, such as LOC4331062, LOC4333870. This study offers insights into molecular transcriptomic impacts seedlings. It provides new perspective further exploration irradiation-induced repair factors understanding reasons mutations created by plants.

Язык: Английский

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Prognostic value of PARP1 and PARP2 copy number alterations in prostate cancer

Laboratory Investigation, Год журнала: 2025, Номер unknown, С. 104171 - 104171

Опубликована: Апрель 1, 2025

Язык: Английский

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Leveraging PARP-1/2 to Target Distant Metastasis

International Journal of Molecular Sciences, Год журнала: 2024, Номер 25(16), С. 9032 - 9032

Опубликована: Авг. 20, 2024

Poly (ADP-Ribose) Polymerase (PARP) inhibitors have changed the outcomes and therapeutic strategy for several cancer types. As a targeted mainly patients with

Язык: Английский

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Oxidative stress and PARP activation in the lungs is an early event in COVID-19 pneumonia

medRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Сен. 4, 2024

Abstract Oxidative stress and poly(ADP-ribosyl)ation (PARylation) leads to tissue damage inflammation in multiple lung diseases, likely COVID-19. In a previous study we evidenced PARylation pulmonary cell types patients who died of COVID-19, but not non-COVID-19 causes. We extended these observations this retrospective immunohistochemical by enlarging stratifying the population. showed that oxidative peaked exudative then decreased proliferative phase. Pulmonary correlated with serum markers liver kidney damage, oxygen transport, hypoxia, lymphocytopenia, blood clotting disseminated intravascular coagulation. Most correlations between chemistry readouts were identified viral load tissues, however, correlation was marginal suggesting presence SARS-CoV-2 can independently induce PARylation. males time hospitalization (time death) inversely Furthermore, males, ∼15 years younger than females, there no difference genders at death. Taken together, manifests early, phase COVID-19 contributes worse clinical outcome for males. These results suggest repurposing pharmacological PARP inhibitors acute counteract damage.

Язык: Английский

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Gel electrophoretic analysis of protein-DNA complexes to classify inhibitors of poly(ADP-ribose) polymerases 1 and 2

Vestnik Moskovskogo universiteta Seria 16 Biologia, Год журнала: 2024, Номер 79(№4, 2024), С. 322 - 329

Опубликована: Янв. 1, 2024

Poly(ADP-ribose) polymerases 1 and 2 (PARP1 PARP2) play an important role in repairing DNA, their inhibition is being used to treat certain oncological diseases. New inhibitors of PARP are actively developed the mechanisms action studied. In present work, using talazoparib, olaparib veliparib, as example, it shown that electrophoresis DNA complexes with PARP1 PARP2 polyacrylamide gel presence makes possible identify effect on affinity enzymes after adding NAD+ substrate, evaluate catalytic activity enzymes. When selecting new for biomedical research, consider these against PARP2.

Язык: Английский

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