SAMHD1 expression contributes to doxorubicin resistance and predicts survival outcomes in diffuse large B-cell lymphoma patients DOI Creative Commons
Waaqo Daddacha, Dominique Monroe, Ashley J. Schlafstein

et al.

NAR Cancer, Journal Year: 2024, Volume and Issue: 6(1)

Published: Jan. 9, 2024

Abstract Diffuse large B-cell lymphoma (DLBCL) is a commonly diagnosed, aggressive non-Hodgkin's lymphoma. While R-CHOP chemoimmunotherapy potentially curative, about 40% of DLBCL patients will fail, highlighting the need to identify biomarkers optimize management. SAMHD1 has dNTPase-independent role in promoting resection facilitate DNA double-strand break (DSB) repair by homologous recombination. We evaluated relationship levels with sensitivity DSB-sensitizing agents cells and association expression clinical outcomes 79 treated definitive therapy an independent cohort dataset 234 patients. Low expression, Vpx-mediated, or siRNA-mediated degradation/depletion was associated greater doxorubicin PARP inhibitors. On Kaplan–Meier log-rank survival analysis, low improved overall (OS), which on subset analysis remained significant only advanced stage (III-IV) moderate high risk (2–5 International Prognostic Index (IPI)). The OS multivariate other adverse factors, including IPI, validated cohort. Our findings suggest that mediates resistance may be important prognostic biomarker advanced, higher-risk

Language: Английский

Sirtuins in kidney diseases: potential mechanism and therapeutic targets DOI Creative Commons
Qi Jin, Fang Ma, Tong‐Tong Liu

et al.

Cell Communication and Signaling, Journal Year: 2024, Volume and Issue: 22(1)

Published: Feb. 12, 2024

Abstract Sirtuins, which are NAD + -dependent class III histone deacetylases, involved in various biological processes, including DNA damage repair, immune inflammation, oxidative stress, mitochondrial homeostasis, autophagy, and apoptosis. Sirtuins essential regulators of cellular function organismal health. Increasing evidence suggests that the development age-related diseases, kidney is associated with aberrant expression sirtuins, regulation sirtuins activity can effectively improve delay progression disease. In this review, we summarise current studies highlighting role renal diseases. First, discuss sirtuin family members their main mechanisms action. We then outline possible roles cell types Finally, compounds activate or inhibit consequently ameliorate conclusion, targeted modulation a potential therapeutic strategy for

Language: Английский

Citations

11
Targeting sirtuins for cancer therapy: epigenetics modifications and beyond DOI Creative Commons
Hui Shen,

Xinyi Qi,

Yue Hu

et al.

Theranostics, Journal Year: 2024, Volume and Issue: 14(17), P. 6726 - 6767

Published: Jan. 1, 2024

Sirtuins (SIRTs) are well-known as nicotinic adenine dinucleotide

Language: Английский

Citations

9
Activation and inhibition of sirtuins: From bench to bedside DOI Creative Commons
Francesco Fiorentino, Emanuele Fabbrizi, Antonello Mai

et al.

Medicinal Research Reviews, Journal Year: 2024, Volume and Issue: unknown

Published: Aug. 31, 2024

Abstract The sirtuin family comprises seven NAD + ‐dependent enzymes which catalyze protein lysine deacylation and mono ADP‐ribosylation. Sirtuins act as central regulators of genomic stability gene expression control key processes, including energetic metabolism, cell cycle, differentiation, apoptosis, aging. As a result, all sirtuins play critical roles in cellular homeostasis organism wellness, their dysregulation has been linked to metabolic, cardiovascular, neurological diseases. Furthermore, have shown dichotomous cancer, acting context‐dependent tumor suppressors or promoters. Given role different attracted increasing research interest aimed at developing both activators inhibitors. Indeed, modulation may therapeutic effects many age‐related diseases, diabetes, cardiovascular neurodegenerative disorders, cancer. Moreover, isoform selective modulators increase our knowledge biology aid develop better therapies. Through this review, we provide insights into pharmacology illustrate enzymatic activities biological functions. outline the most relevant terms modes action, structure–activity relationships, pharmacological effects, clinical applications.

Language: Английский

Citations

6
DNA-PK is activated by SIRT2 deacetylation to promote DNA double-strand break repair by non-homologous end joining DOI Creative Commons
PamelaSara E. Head,

Priya Kapoor-Vazirani,

Ganji Purnachandra Nagaraju

et al.

Nucleic Acids Research, Journal Year: 2023, Volume and Issue: 51(15), P. 7972 - 7987

Published: July 3, 2023

Abstract DNA-dependent protein kinase (DNA-PK) plays a critical role in non-homologous end joining (NHEJ), the predominant pathway that repairs DNA double-strand breaks (DSB) response to ionizing radiation (IR) govern genome integrity. The interaction of catalytic subunit DNA-PK (DNA-PKcs) with Ku70/Ku80 heterodimer on DSBs leads activation; however, it is not known if upstream signaling events this activation. Here, we reveal regulatory step governing activation by SIRT2 deacetylation, which facilitates DNA-PKcs localization and Ku, thereby promoting DSB repair NHEJ. deacetylase activity governs cellular resistance DSB-inducing agents promotes furthermore interacts deacetylates IR. Ku phosphorylation downstream NHEJ substrates. Moreover, targeting AGK2, SIRT2-specific inhibitor, augments efficacy IR cancer cells tumors. Our findings define for SIRT2-mediated elucidating event initiating Furthermore, our data suggest inhibition may be promising rationale-driven therapeutic strategy increasing effectiveness therapy.

Language: Английский

Citations

12
Phosphorylation-driven regulation of SIRT1 in muscle senescence: Insights from molecular dynamics simulation and experimental validation DOI
Siyao Liu, Shan Liang, Yue Li

et al.

International Journal of Biological Macromolecules, Journal Year: 2025, Volume and Issue: 306, P. 141734 - 141734

Published: March 6, 2025

Language: Английский

Citations

0
Mechanisms and regulation of DNA end resection in the maintenance of genome stability DOI
Raphaël Ceccaldi, Petr Ćejka

Nature Reviews Molecular Cell Biology, Journal Year: 2025, Volume and Issue: unknown

Published: March 25, 2025

Language: Английский

Citations

0
Transcriptomic Analysis Reveals Key Pathways Influenced by HIV-2 Vpx DOI Open Access
Zsófia Ilona Szojka, Balázs Kunkli,

Irene Wanjiru Kiarie

et al.

International Journal of Molecular Sciences, Journal Year: 2025, Volume and Issue: 26(8), P. 3460 - 3460

Published: April 8, 2025

Viral protein X (Vpx) is a unique accessory encoded by the genome of human immunodeficiency virus type 2 (HIV-2) and lineages simian sooty mangabeys. So far, counteracting cellular restriction factor SAMHD1 mediating efficient translocation viral pre-integration complex have been recognized as key functions Vpx; however, thorough exploration its effects on transcriptome cytokine milieu has not yet undertaken. In this study, we carried out transcriptomic analysis THP-1 cells determined differential gene expressions induced HIV-2 Vpx, utilizing vectors coding for wild-type K68-R70 functionally restricted proteins. Significantly altered genes were then validated quantified through real-time quantitative PCR (qPCR); additionally, replication-competent virions also used to confirm findings. Moreover, analyzed effect Vpx expression secretion cytokines in medium transfected cells. Our findings revealed that can significantly alter helicases, zinc finger proteins, chaperons, transcription factors proteins involved DNA methylation. Differentially negative regulation processes, I interferon-signaling pathway, DNA-template transcription, elongation, positive interferon beta production innate immune response. Importantly, was found decrease HIV-1 Tat, possibly downregulation crucial splicing factor, required maturation Tat. Additionally, studies showed proinflammatory cytokines. study provides important information about role played priming taming environment allow establishment infection.

Language: Английский

Citations

0
dNTP depletion and beyond: the multifaceted nature of SAMHD1-mediated viral restriction DOI Creative Commons
Pak‐Hin Hinson Cheung, Hua Yang, Li Wu

et al.

Journal of Virology, Journal Year: 2025, Volume and Issue: unknown

Published: April 25, 2025

ABSTRACT SAMHD1 is a dNTPase of mammalian cells. In 2011, was found to be host restriction factor against retroviruses through dNTP reduction. Recent research provides evidence that the antiviral mechanisms cannot explained solely by its activity. Instead, versatility SAMHD1-mediated various viruses suggests extend beyond depletion. This explains multifaceted and broad functions play significant role in innate immunity.

Language: Английский

Citations

0
Therapeutic applications of exercise in neurodegenerative diseases: focusing on the mechanism of SIRT1 DOI
Jingwen Li, Tingting Liu,

Meiyan Xian

et al.

Molecular and Cellular Biochemistry, Journal Year: 2025, Volume and Issue: unknown

Published: May 13, 2025

Language: Английский

Citations

0
Understanding the interplay between dNTP metabolism and genome stability in cancer DOI Creative Commons
Miriam Yagüe-Capilla, Sean G. Rudd

Disease Models & Mechanisms, Journal Year: 2024, Volume and Issue: 17(8)

Published: Aug. 1, 2024

ABSTRACT The size and composition of the intracellular DNA precursor pool is integral to maintenance genome stability, this relationship fundamental our understanding cancer. Key aspects carcinogenesis, including elevated mutation rates induction certain types damage in cancer cells, can be linked disturbances deoxynucleoside triphosphate (dNTP) pools. Furthermore, approaches treat heavily exploit metabolic interplay between dNTP pool, with a long-standing example being use antimetabolite-based therapies, strategy continues show promise development new targeted therapies. In Review, we compile current knowledge on both causes consequences perturbations together their impact stability. We outline several outstanding questions remaining field, such as role catabolism stability expansion. Importantly, detail how mechanistic these processes utilised aim providing better informed treatment options patients

Language: Английский

Citations

3