Mechanisms of genotoxicity and proteotoxicity induced by the metalloids arsenic and antimony DOI Creative Commons
Robert Wysocki, Joana Isabel Rodrigues, Ireneusz Litwin

et al.

Cellular and Molecular Life Sciences, Journal Year: 2023, Volume and Issue: 80(11)

Published: Oct. 30, 2023

Abstract Arsenic and antimony are metalloids with profound effects on biological systems human health. Both elements toxic to cells organisms, exposure is associated several pathological conditions including cancer neurodegenerative disorders. At the same time, arsenic- antimony-containing compounds used in treatment of multiple diseases. Although these can both cause cure disease, their modes molecular action incompletely understood. The past decades have seen major advances our understanding arsenic toxicity, emphasizing genotoxicity proteotoxicity as key contributors pathogenesis. In this review, we highlight mechanisms by which focusing genotoxic proteotoxic effects. maintain proteostasis during metalloid also described. Furthermore, address how metalloid-induced may promote disease be interrelated together contribute proteinopathies. A deeper cellular toxicity response links pathogenesis development strategies for prevention treatment.

Language: Английский

Advances of Epigenetic Biomarkers and Epigenome Editing for Early Diagnosis in Breast Cancer DOI Open Access
Pourya Sarvari, Pouya Sarvari, Ivonne Ramírez‐Díaz

et al.

International Journal of Molecular Sciences, Journal Year: 2022, Volume and Issue: 23(17), P. 9521 - 9521

Published: Aug. 23, 2022

Epigenetic modifications are known to regulate cell phenotype during cancer progression, including breast cancer. Unlike genetic alterations, changes in the epigenome reversible, thus potentially reversed by epi-drugs. Breast cancer, most common cause of death worldwide women, encompasses multiple histopathological and molecular subtypes. Several lines evidence demonstrated distortion epigenetic landscape Interestingly, mammary cells isolated from patients cultured ex vivo maintained tumorigenic exhibited aberrant modifications. Recent studies indicated that therapeutic efficiency for regimens has increased over time, resulting reduced mortality. Future medical treatment patients, however, will likely depend upon a better understanding The present review aims outline different mechanisms DNA methylation, histone modifications, ncRNAs with their impact on as well discuss highlighting central role pathogenesis. We propose new research areas may facilitate locus-specific editing therapeutics.

Language: Английский

Citations

32
Transcription factor condensates and signaling driven transcription DOI Creative Commons

Rajat Mann,

Dimple Notani

Nucleus, Journal Year: 2023, Volume and Issue: 14(1)

Published: May 2, 2023

Transcription Factor (TF) condensates are a heterogenous mix of RNA, DNA, and multiple co-factor proteins capable modulating the transcriptional response cell. The dynamic nature spatial location TF-condensates in 3D nuclear space is believed to provide fast response, which on same pace as signaling cascade yet ever-so-specific crowded environment nucleus. However, current understanding how can achieve these feet so quickly efficiently still unclear. In this review, we draw parallels with other protein share our speculations nucleus uses high specificity fidelity. We discuss various constituents TF-condensates, their properties, known unknown functions particular focus steroid signaling-induced programs.

Language: Английский

Citations

20
Liquid-liquid phase separation in DNA double-strand breaks repair DOI Creative Commons
Yunlong Wang, Wan-Wen Zhao,

Jie Shi

et al.

Cell Death and Disease, Journal Year: 2023, Volume and Issue: 14(11)

Published: Nov. 15, 2023

Abstract DNA double-strand breaks (DSBs) are the fatal type of damage mostly induced by exposure genome to ionizing radiation or genotoxic chemicals. DSBs mainly repaired homologous recombination (HR) and nonhomologous end joining (NHEJ). To repair DSBs, a large amount factors was observed be concentrated at in specific spatiotemporal manner form center. Recently, this center characterized as condensate derived from liquid-liquid phase separation (LLPS) key factors. LLPS has been found mechanism membraneless organelles formation plays roles variety biological processes. In review, recent advances mechanisms repair-related condensates summarized.

Language: Английский

Citations

20
Compartmentalization of the DNA damage response: Mechanisms and functions DOI Creative Commons
Emile Alghoul, Jihane Basbous, Angelos Constantinou

et al.

DNA repair, Journal Year: 2023, Volume and Issue: 128, P. 103524 - 103524

Published: June 10, 2023

Cells have evolved an arsenal of molecular mechanisms to respond continuous alterations in the primary structure DNA. At cellular level, DNA damage response proteins accumulate at sites and organize into nuclear foci. As recounted by Errol Friedberg, pioneering work on repair 1930 s was stimulated collaborations between physicists geneticists. In recent years, introduction ideas from physics self-organizing compartments has taken field cell biology storm. Percolation phase separation theories are increasingly used model self-assembly compartments, called biomolecular condensates, that selectively concentrate molecules without a surrounding membrane. this review, we discuss these concepts context response. We how studies foci as condensates can link with physiological functions, provide new insights regulatory mechanisms, open perspectives for targeting responses therapeutic purposes.

Language: Английский

Citations

18
Fluorescence and phosphorescence lifetime imaging reveals a significant cell nuclear viscosity and refractive index changes upon DNA damage DOI Creative Commons
Ellen Clancy,

Siva Ramadurai,

Sarah R. Needham

et al.

Scientific Reports, Journal Year: 2023, Volume and Issue: 13(1)

Published: Jan. 9, 2023

Abstract Cytoplasmic viscosity is a crucial parameter in determining rates of diffusion-limited reactions. Changes are associated with several diseases, whilst nuclear determines gene integrity, regulation and expression. Yet how drugs including DNA-damaging agents affect unknown. We demonstrate the use platinum complex, Pt[L]Cl, that localizes efficiently mostly nucleus as probe for viscosity. The phosphorescence lifetime Pt[L]Cl sensitive to provides an excellent tool investigate impact DNA damage. show using Fluorescence Lifetime Imaging (FLIM) both green red fluorescent proteins (FP) also changes cellular refractive index. However, proved be more probe, by virtue microsecond versus nanosecond fluorescence FP, hence greater sensitivity bimolecular damage was inflicted either two-photon excitation, one-photon excitation microbeam X-rays. live cells causes significant increase (HeLa cells, 12.5–14.1 µs) or intracellularly expressed mCherry (HEK293 1.54–1.67 ns), but decrease GFP from 2.65 2.29 ns (in V15B cells). These values represent change 8.59 20.56 cP well index (RI), according independent calibration. Interestingly localized submicron region following laser induction showed whole cell change, those being than cytoplasm. found evidence by-stander effect, whereby adjacent un-irradiated change. Finally, observed bacterial over-expressed mNeonGreen evidenced its 2.8 2.4 ns.

Language: Английский

Citations

17
A comprehensive review on DDX3X liquid phase condensation in health and neurodevelopmental disorders DOI
Ivan Rosa e Silva, Juliana Helena Costa Smetana, Juliana Ferreira de Oliveira

et al.

International Journal of Biological Macromolecules, Journal Year: 2024, Volume and Issue: 259, P. 129330 - 129330

Published: Jan. 11, 2024

Language: Английский

Citations

6
Intrinsic factors behind long COVID: IV. Hypothetical roles of the SARS‐CoV‐2 nucleocapsid protein and its liquid–liquid phase separation DOI

Ahmed Eltayeb,

Faisal Al‐Sarraj, Mona G. Alharbi

et al.

Journal of Cellular Biochemistry, Journal Year: 2024, Volume and Issue: 125(3)

Published: Feb. 13, 2024

Abstract When the SARS‐CoV‐2 virus infects humans, it leads to a condition called COVID‐19 that has wide spectrum of clinical manifestations, from no symptoms acute respiratory distress syndrome. The initiates damage by attaching ACE‐2 protein on surface endothelial cells line blood vessels and using these as hosts for replication. Reactive oxygen species levels are increased during viral replication, which oxidative stress. About three‐fifths (~60%) people who get infected with eradicate their body after 28 days recover normal activity. However, large fraction (~40%) suffer various (anosmia and/or ageusia, fatigue, cough, myalgia, cognitive impairment, insomnia, dyspnea, tachycardia) beyond 12 weeks diagnosed syndrome long COVID. Long‐term studies in group contracted have been contrasted noninfected matched people. A subset can be distinguished set cytokine markers persistent, low‐grade inflammation often self‐report two or more bothersome symptoms. No medication alleviate efficiently. Coronavirus nucleocapsid proteins investigated extensively potential drug targets due key roles among is ability bind respective genomic RNAs incorporation into emerging virions. This review highlights basic its undergo liquid–liquid phase separation. We hypothesize this separation may contribute hypothesis unlocks new investigation angles could potentially open novel avenues better understanding COVID treating condition.

Language: Английский

Citations

6
Regulation of Biomolecular Condensates by Poly(ADP-ribose) DOI
Kevin Rhine, Hana M. Odeh, James Shorter

et al.

Chemical Reviews, Journal Year: 2023, Volume and Issue: 123(14), P. 9065 - 9093

Published: April 28, 2023

Biomolecular condensates are reversible compartments that form through a process called phase separation. Post-translational modifications like ADP-ribosylation can nucleate the formation of these by accelerating self-association proteins. Poly(ADP-ribose) (PAR) chains remarkably transient with turnover rates on order minutes, yet they be required for granules in response to oxidative stress, DNA damage, and other stimuli. Moreover, accumulation PAR is linked adverse transitions neurodegenerative diseases, including Alzheimer's disease, Parkinson's amyotrophic lateral sclerosis. In this review, we provide primer how synthesized regulated, diverse structures chemistries modifications, protein–PAR interactions. We review substantial progress recent efforts determine molecular mechanism PAR-mediated separation, further delineate inhibitors polymerases may effective treatments pathologies. Finally, highlight need rigorous biochemical interrogation vivo vitro clarify exact pathway from PARylation condensate formation.

Language: Английский

Citations

16
Liquid‒liquid phase separation: roles and implications in future cancer treatment DOI Creative Commons
Zheran Liu, Zijian Qin,

Yingtong Liu

et al.

International Journal of Biological Sciences, Journal Year: 2023, Volume and Issue: 19(13), P. 4139 - 4156

Published: Jan. 1, 2023

Liquid-liquid phase separation (LLPS) is a phenomenon driven by weak interactions between biomolecules, such as proteins and nucleic acids, that leads to the formation of distinct liquid-like condensates.Through LLPS, membraneless condensates are formed, selectively concentrating specific while excluding other molecules maintain normal cellular functions.Emerging evidence shows cancer-related mutations cause aberrant condensate assembly, resulting in disrupted signal transduction, impaired DNA repair, abnormal chromatin organization eventually contributing tumorigenesis.The objective this review summarize recent advancements understanding potential implications LLPS contexts cancer progression therapeutic interventions.By interfering with it may be possible restore processes inhibit tumor progression.The underlying mechanisms drug targets associated discussed, shedding light on promising opportunities for novel interventions.

Language: Английский

Citations

16
The pleiotropic nature of NONO, a master regulator of essential biological pathways in cancers DOI Creative Commons
Domenica Ronchetti, Valentina Traini,

Ilaria Silvestris

et al.

Cancer Gene Therapy, Journal Year: 2024, Volume and Issue: 31(7), P. 984 - 994

Published: March 16, 2024

Abstract NONO is a member of the Drosophila behavior/human splicing (DBHS) family proteins. multifunctional protein that acts as “molecular scaffold” to carry out versatile biological activities in many aspects gene regulation, cell proliferation, apoptosis, migration, DNA damage repair, and maintaining cellular circadian rhythm coupled cycle. Besides these physiological activities, emerging evidence strongly indicates NONO-altered expression levels promote tumorigenesis. In addition, can undergo various post-transcriptional or post-translational modifications, including alternative splicing, phosphorylation, methylation, acetylation, whose impact on cancer remains largely be elucidated. Overall, altered and/or are common feature cancer. This review provides an integrated scenario current understanding molecular mechanisms processes affected by different tumor contexts, suggesting better elucidation pleiotropic functions physiology tumorigenesis will make it potential therapeutic target this respect, due complex landscape interactions, we highlight caveats must considered during experimental planning data interpretation studies.

Language: Английский

Citations

6