The Influence of Circadian Rhythms on DNA Damage Repair in Skin Photoaging

International Journal of Molecular Sciences, Год журнала: 2024, Номер 25(20), С. 10926 - 10926

Опубликована: Окт. 11, 2024

Circadian rhythms, the internal timekeeping systems governing physiological processes, significantly influence skin health, particularly in response to ultraviolet radiation (UVR). Disruptions circadian rhythms can exacerbate UVR-induced damage and increase risk of aging cancer. This review explores how affect various aspects physiology pathology, with a special focus on DNA repair. regulation ensures optimal repair following damage, reducing mutation accumulation, enhancing genomic stability. The control over cell proliferation apoptosis further contributes regeneration UVR. Oxidative stress management is another critical area where exert influence. Key genes like brain muscle ARNT-like 1 (BMAL1) locomotor output cycles kaput (CLOCK) modulate activity antioxidant enzymes signaling pathways protect cells from oxidative stress. also inflammatory immune responses by modulating Langerhans other skin. In summary, form complex defense network that manages through precise repair, proliferation, apoptosis, response, stress, hormonal signaling. Understanding these mechanisms provides insights into developing targeted protection improving cancer prevention.

Язык: Английский

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USP1 deubiquitinates PARP1 to regulate its trapping and PARylation activity

Science Advances, Год журнала: 2024, Номер 10(46)

Опубликована: Ноя. 13, 2024

PARP inhibitors (PARPi) represent a game-changing treatment for patients with ovarian cancer tumors deficient the homologous recombination (HR) pathway treated platinum (Pt)-based therapy. PARPi exert their cytotoxic effect by both trapping PARP1 on damaged DNA and restraining its enzymatic activity (PARylation). How is recruited trapped at damage sites how resistance to could be overcome are still matters of investigation. Here, we described as substrate deubiquitinase USP1. At molecular level, USP1 binds remove K63-linked polyubiquitination controls chromatin PARylation activity, regulating sensitivity PARPi. In Pt/PARPi-sensitive -resistant cells, USP1/PARP1 combined blockade enhances replicative stress, damage, cell death. Our work dissected biological interaction between recommended this axis promising powerful therapeutic choice not only sensitive but also chemoresistant irrespective HR status.

Язык: Английский

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Co-Targeting of DTYMK and PARP1 as a Potential Therapeutic Approach in Uveal Melanoma

Cells, Год журнала: 2024, Номер 13(16), С. 1348 - 1348

Опубликована: Авг. 14, 2024

Uveal melanoma (UM) is the most common primary intraocular tumor in adults, with no standardized treatment for advanced disease. Based on preliminary bioinformatical analyses DTYMK and PARP1 were selected as potential therapeutic targets. High levels of both proteins detected uveal cells correlated increased growth poor prognosis. In vitro tests MP41 (BAP1 positive) MP46 negative) cancer cell lines using inhibitors pamiparib (PARP1) Ymu1 (DTYMK) demonstrated significant cytotoxic effects. Combined had synergistic effects additive lines, reducing proliferation inhibiting mTOR signaling pathway. Furthermore, applied combination decreased motility migration speed, especially BAP1-negative lines. Our hypothesis double hit into tumoral DNA metabolism a possible option was confirmed since combined targeting affected all tested cytophysiological parameters highest efficiency. findings provide insights novel avenues managing melanoma, warranting further exploration preclinical clinical settings.

Язык: Английский

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NMNAT1 Is Essential for Human iPS Cell Differentiation to the Retinal Lineage

Investigative Ophthalmology & Visual Science, Год журнала: 2024, Номер 65(12), С. 37 - 37

Опубликована: Окт. 24, 2024

The gene encoding nicotinamide mononucleotide adenylyltransferase 1 (NMNAT1), a adenine dinucleotide synthetase localized in the cell nucleus, is causative factor Leber's congenital amaurosis, which earliest onset type of inherited retinal degeneration. We sought to investigate roles NMNAT1 early development.

Язык: Английский

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SART1 modulates Poly-(ADP-Ribose) chain accumulation and PARP1 chromatin localization

iScience, Год журнала: 2024, Номер 27(11), С. 111252 - 111252

Опубликована: Окт. 24, 2024

Язык: Английский

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Development of novel flavonoid senolytics through phenotypic drug screening and drug design

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

Опубликована: Окт. 27, 2024

Abstract Accumulation of senescent cells drives aging and age-related diseases. Senolytics, which selectively kill cells, offer a promising approach for treating many Using cell-based phenotypic drug discovery that combines screening design, we developed two novel flavonoid senolytics, SR29384 SR31133, derived from the senolytic fisetin. These compounds demonstrated enhanced activities, effectively eliminating multiple cell types, reducing tissue senescence in vivo , extending healthspan mouse model accelerated aging. Mechanistic studies utilizing RNA-Seq, machine learning, network pharmacology, computational simulation suggest these senolytics target PARP1, BCL-xL, CDK2 to induce selective death. This phenotype-based coupled with mechanistic insights, represents key advancement developing next-generation senolyticss potential clinical applications

Язык: Английский

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The CYLD–PARP1 feedback loop regulates DNA damage repair and chemosensitivity in breast cancer cells

Proceedings of the National Academy of Sciences, Год журнала: 2024, Номер 122(1)

Опубликована: Дек. 31, 2024

Poly(ADP-ribose) polymerase 1 (PARP1) plays a crucial role in DNA repair and genomic stability maintenance. However, the regulatory mechanisms governing PARP1 activity, particularly through deubiquitination, remain poorly elucidated. Using deubiquitinase (DUB) library binding screen, we identified cylindromatosis (CYLD) as bona fide DUB for breast cancer cells. Mechanistically, CYLD is recruited by to lesions upon genotoxic stress, where it cleaves K63-linked polyubiquitin chains on at residues K748, K940, K949, resulting compromised activation. In reciprocal manner, PARylates sites E191, E231, E259, E509, thereby enhancing its activity. Consequently, depletion of leads increased efficiency base excision confers cells with resistance alkylating agents. Conversely, overexpression enhances sensitivity PARP inhibitors (PARPi) even homologous recombination-proficient These findings offer unique insights into intricate interplay between repair, underscoring pivotal targeting this axis chemotherapy.

Язык: Английский

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How Banf1 Functions to Inhibit the Activity of PARP1

Опубликована: Янв. 1, 2024

This thesis explores the interaction between two key proteins, Banf1 and PARP1, which play crucial roles in DNA repair. Using advanced techniques like mass photometry, spectroscopy, electron microscopy, research reveals how regulates PARP1's activity by binding to its catalytic domain. is significant for maintaining genomic stability, with implications diseases such as cancer, where repair processes are often disrupted. The findings contribute understanding these proteins function together, potentially paving way new therapeutic strategies targeting PARP1 cancer treatment.

Язык: Английский

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Investigating Protein Binding with the Isothermal Ligand‐induced Resolubilization Assay

ChemBioChem, Год журнала: 2024, Номер 25(6)

Опубликована: Янв. 24, 2024

Abstract Target engagement assays typically detect and quantify the direct physical interaction of a protein interest its ligand through stability changes upon binding. Commonly used target methods ligand‐induced by subjecting samples to thermal or proteolytic stress. Here we describe new variation these approaches called Isothermal Ligand‐induced Resolubilization Assay (ILIRA), which utilizes lyotropic solubility stress measure binding in solubility. We identified distinct buffer systems salt concentrations that compromised for four diverse proteins: dihydrofolate reductase (DHFR), nucleoside diphosphate‐linked moiety X motif 5 (NUDT5), poly [ADP‐ribose] polymerase 1 (PARP1), arginine N ‐methyltransferase (PRMT1). rescue was demonstrated proteins, suggesting ILIRA can be as an additional technique. Differences were assessed Coomassie blue staining SDS‐PAGE dot blot, well NanoOrange, Thioflavin T, Proteostat fluorescence, thus offering flexibility readout assay throughput.

Язык: Английский

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Roles of DNMT3B and PARP1 Genes Expression in Cytogenetically Normal Acute Myeloid Leukemia

Clinical Medicine Insights Oncology, Год журнала: 2024, Номер 18

Опубликована: Янв. 1, 2024

Background: Acute myeloid leukemia (AML) has a heterogeneous molecular profile, clinical presentations, and response to treatments outcomes. DNA methylation is conducted by methyltransferases including DNMT3B. Poly ADP-ribose polymerase 1 belongs family of enzymes that mediate important cellular processes repair, transcription, cell death/cell proliferation, it involved in the development, spread, treatment, prognosis some cancers. The objective this study assess impact PARP1 DNMT3B genes expression on laboratory characteristics, treatment survival Egyptian cytogenetically normal AML patients. Methods: This included 67 CN-AML patients addition 8 healthy bone marrow donors. Measurement gene was done samples via real-time semiquantitative chain reaction. Result: Expression both significantly upregulated ( P = .001, .036, respectively). Upregulated associated with higher total leukocyte count (TLC), PB, BM blast cell%. Also, correlated TLC, High greater frequencies FLT3-ITD. expression, combined upregulation ELN stratification. But no correlation found (CR), overall (OS), disease-free (DFS), or event-free (EFS). Conclusion: Our findings highlight importance considering levels as potential prognostic biomarkers for progression aggressiveness AML. Assessing their could be an indicator guide decisions potentially improve patient

Язык: Английский

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