The Global Phosphorylation Landscape of SARS-CoV-2 Infection

Cell, Journal Year: 2020, Volume and Issue: 182(3), P. 685 - 712.e19

Published: June 28, 2020

Language: Английский

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How cells ensure correct repair of DNA double-strand breaks

Journal of Biological Chemistry, Journal Year: 2018, Volume and Issue: 293(27), P. 10502 - 10511

Published: Feb. 8, 2018

DNA double-strand breaks (DSBs) arise regularly in cells and when left unrepaired cause senescence or cell death. Homologous recombination (HR) nonhomologous end-joining (NHEJ) are the two major DNA-repair pathways. Whereas HR allows faithful DSB repair healthy growth, NHEJ has higher potential to contribute mutations malignancy. Many regulatory mechanisms influence which of these pathways is used repair. These depend on cycle, post-translational modifications, chromatin effects. Here, we summarize current research into mechanisms, with a focus mammalian cells, also discuss by "alternative end-joining" single-strand annealing.

Language: Английский

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Methods Favoring Homology-Directed Repair Choice in Response to CRISPR/Cas9 Induced-Double Strand Breaks

International Journal of Molecular Sciences, Journal Year: 2020, Volume and Issue: 21(18), P. 6461 - 6461

Published: Sept. 4, 2020

Precise gene editing is—or will soon be—in clinical use for several diseases, and more applications are under development. The programmable nuclease Cas9, directed by a single-guide RNA (sgRNA), can introduce double-strand breaks (DSBs) in target sites of genomic DNA, which constitutes the initial step using this novel technology. In mammals, two pathways dominate repair DSBs—nonhomologous end joining (NHEJ) homology-directed (HDR)—and outcome mainly depends on choice between these pathways. Although HDR is attractive its high fidelity, pathway biased biological context. Mammalian cells preferentially employ NHEJ over through mechanisms: active throughout cell cycle, whereas restricted to S/G2 phases; faster than HDR; suppresses process. This suggests that definitive control programmed DNA lesioning could be achieved manipulating cellular pathway. review, we summarize DSB pathways, mechanisms involved selection based resection, make progress research investigating strategies favor Cas9-mediated manipulation increase frequency mammalian cells. remaining problems improving efficiency also discussed. review should facilitate development CRISPR/Cas9 technology achieve precise editing.

Language: Английский

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Cyclin E/CDK2: DNA Replication, Replication Stress and Genomic Instability

Frontiers in Cell and Developmental Biology, Journal Year: 2021, Volume and Issue: 9

Published: Nov. 24, 2021

DNA replication must be precisely controlled in order to maintain genome stability. Transition through cell cycle phases is regulated by a family of Cyclin-Dependent Kinases (CDKs) association with respective cyclin regulatory subunits. In normal cycles, E-type cyclins (Cyclin E1 and Cyclin E2, CCNE1 CCNE2 genes) associate CDK2 promote G1/S transition. E/CDK2 complex mostly controls progression phosphorylation specific substrates. Oncogenic activation impairs replication, causing stress damage. As consequence, E/CDK2-induced leads genomic instability contributes human carcinogenesis. this review, we focus on the main functions molecular mechanisms which oncogenic causes cancer.

Language: Английский

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Cyclin-dependent kinases in DNA damage response

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer, Journal Year: 2022, Volume and Issue: 1877(3), P. 188716 - 188716

Published: March 7, 2022

The cyclin-dependent kinase (CDK) family plays a critical role in variety of signaling pathways that regulate transcription and cell-cycle progression. Recently, the CDKs DNA damage response (DDR) has emerged. affect both repair, contributing to fidelity cell division process as well maintenance genomic integrity following damage. This is due modulatory on double-strand break repair (DSBR) components, including their influence enzymes involved homologous recombination (HR) non-homologous end-joining (NHEJ). In this review, impact DDR discussed.

Language: Английский

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Loss of ARID1A in Tumor Cells Renders Selective Vulnerability to Combined Ionizing Radiation and PARP Inhibitor Therapy

Clinical Cancer Research, Journal Year: 2019, Volume and Issue: 25(18), P. 5584 - 5594

Published: June 13, 2019

Somatic inactivating mutations in ARID1A, a component of the SWI/SNF chromatin remodeling complex, are detected various types human malignancies. Loss ARID1A compromises DNA damage repair. The induced burden may increase reliance on PARP-dependent repair cancer cells to maintain genome integrity and render susceptibility PARP inhibitor therapy.Experimental Design: Isogenic ARID1A-/- wild-type cell lines were used for assessing response, compactness, profiling global serine/threonine phosphoproteomic vivo. A panel inhibitors targeting pathways was screened synergistic antitumor effect with irradiation tumors.ARID1A-deficient endometrial exhibit sustained levels result further supported by vivo analysis. Our results show that is essential establishing an open state upon damage, process required recruitment 53BP1 RIF1, key mediators non-homologous end-joining (NHEJ) machinery, lesions. inability mount NHEJ partial cytotoxic response radiation. Small-molecule compound screens revealed act synergistically radiation potentiate cytotoxicity cells. Combination treatment low-dose olaparib greatly improved efficacy, resulting long-term remission mice bearing ARID1A-deficient acquire high sensitivity inhibition after exposure exogenously breaks such as ionizing findings suggest novel biologically informed strategy treating

Language: Английский

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An inventory of crosstalk between ubiquitination and other post-translational modifications in orchestrating cellular processes

iScience, Journal Year: 2023, Volume and Issue: 26(5), P. 106276 - 106276

Published: Feb. 26, 2023

Ubiquitination is an important post-translational modification (PTM) that regulates a large spectrum of cellular processes in eukaryotes. Abnormalities ubiquitin signaling underlie numerous human pathologies including cancer and neurodegeneration. Much progress has been made during the last three decades understanding how ligases recognize their substrates ubiquitination orchestrated. Several mechanisms regulation have evolved to prevent promiscuity assembly multi-protein complexes with dedicated subunits specific modifications these enzymes co-factors. Here, we outline another layer complexity involving coordinated access E3 substrates. We provide extensive inventory crosstalk multiple PTMs SUMOylation, phosphorylation, methylation, acetylation, hydroxylation, prolyl isomerization, PARylation, O-GlcNAcylation. discuss molecular by which orchestrate ubiquitination, thus increasing its specificity as well other pathways ensure cell homeostasis.

Language: Английский

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Lipoylation inhibition enhances radiation control of lung cancer by suppressing homologous recombination DNA damage repair

Science Advances, Journal Year: 2025, Volume and Issue: 11(11)

Published: March 12, 2025

Lung cancer exhibits altered metabolism, influencing its response to radiation. To investigate the metabolic regulation of radiation response, we conducted a comprehensive, metabolic-wide CRISPR-Cas9 loss-of-function screen using as selection pressure in human non–small cell lung cancer. Lipoylation emerged key target for radiosensitization, with lipoyltransferase 1 (LIPT1) identified top hit. LIPT1 covalently conjugates mitochondrial 2-ketoacid dehydrogenases lipoic acid, facilitating enzymatic functions involved tricarboxylic acid cycle. Inhibiting lipoylation, either through genetic knockout or lipoylation inhibitor (CPI-613), enhanced tumor control by Mechanistically, inhibition increased 2-hydroxyglutarate, leading H3K9 trimethylation, disrupting TIP60 recruitment and ataxia telangiectasia mutated (ATM)–mediated DNA damage repair signaling, impairing homologous recombination repair. In summary, our findings reveal critical role regulating chromosome stability may suggest means enhance therapeutic outcomes DNA-damaging agents.

Language: Английский

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DNA-PKcs promotes chromatin decondensation to facilitate initiation of the DNA damage response

Nucleic Acids Research, Journal Year: 2019, Volume and Issue: 47(18), P. 9467 - 9479

Published: July 31, 2019

The DNA damage response (DDR) encompasses the cellular to double-stranded breaks (DSBs), and includes recognition of DSB, recruitment numerous factors site, initiation signaling cascades, chromatin remodeling, cell-cycle checkpoint activation, repair DSB. Key drivers DDR are multiple members phosphatidylinositol 3-kinase-related kinase family, including ataxia telangiectasia mutated (ATM), Rad3-related (ATR), DNA-dependent protein catalytic subunit (DNA-PKcs). ATM ATR modulate portions DDR, but DNA-PKcs is believed primarily function in DSB pathway, non-homologous end joining. Utilizing a human cell line which domain inactivated, we show here that activity required for DSBs immediately after their induction. Specifically, initiates phosphorylation H2AX KAP1 following ionizing radiation exposure drives local decondensation near site. Furthermore, loss results marked decrease machinery DSBs. Collectively, these provide clear evidence pivotal DDR.

Language: Английский

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Toward understanding genomic instability, mitochondrial dysfunction and aging

FEBS Journal, Journal Year: 2018, Volume and Issue: 286(6), P. 1058 - 1073

Published: Sept. 21, 2018

The biology of aging is an area intense research, and many questions remain about how why cell organismal functions decline over time. In mammalian cells, genomic instability mitochondrial dysfunction are thought to be among the primary drivers cellular aging. This review focuses on interrelationship between in cells its relevance age‐related functional at molecular level. importance oxidative stress key DNA damage response pathways discussed, with a special focus poly ( ADP ‐ribose) polymerase 1, whose persistent activation depletes energy reserves, leading dysfunction, loss homeostasis, altered metabolism. Elucidation relationship instability, signaling that connect these pathways/processes keys future research human An important component health preservation mitophagy, this other areas particularly ripe for investigation will discussed.

Language: Английский

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