The liquid-to-solid transition of FUS is promoted by the condensate surface

Proceedings of the National Academy of Sciences, Journal Year: 2023, Volume and Issue: 120(33)

Published: Aug. 7, 2023

A wide range of macromolecules can undergo phase separation, forming biomolecular condensates in living cells. These membraneless organelles are typically highly dynamic, formed reversibly, and carry out essential functions biological systems. Crucially, however, a further liquid-to-solid transition the lead to irreversible pathological aggregation cellular dysfunction associated with onset development neurodegenerative diseases. Despite importance this proteins, mechanism by which it is initiated normally functional unknown. Here we show, measuring changes structure, dynamics, mechanics time space, that single-component FUS do not uniformly convert solid gel, but rather liquid gel phases coexist simultaneously within same condensate, resulting inhomogeneous structures. Furthermore, our results show originates at interface between condensate dilute continuous phase, once initiated, gelation process propagates toward center condensate. To probe such spatially rheology during aging, use combination established micropipette aspiration experiments together two optical techniques, spatial dynamic mapping reflective confocal speckle microscopy. reveal spatiotemporal dimension highlight as critical element driving protein aggregation.

Language: Английский

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Phase separation properties of RPA combine high-affinity ssDNA binding with dynamic condensate functions at telomeres

Nature Structural & Molecular Biology, Journal Year: 2023, Volume and Issue: 30(4), P. 451 - 462

Published: March 9, 2023

Abstract RPA has been shown to protect single-stranded DNA (ssDNA) intermediates from instability and breakage. binds ssDNA with sub-nanomolar affinity, yet dynamic turnover is required for downstream transactions. How ultrahigh-affinity binding are achieved simultaneously not well understood. Here we reveal that a strong propensity assemble into condensates. In solution, purified phase separates liquid droplets fusion surface wetting behavior. Phase separation stimulated by sub-stoichiometric amounts of ssDNA, but RNA or double-stranded DNA, gets selectively enriched in We find the RPA2 subunit condensation multi-site phosphorylation N-terminal intrinsically disordered region regulate self-interaction. Functionally, quantitative proximity proteomics links telomere clustering integrity cancer cells. Collectively, our results suggest RPA-coated contained condensates whose properties important genome organization stability.

Language: Английский

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Biological soft matter: intrinsically disordered proteins in liquid–liquid phase separation and biomolecular condensates

Essays in Biochemistry, Journal Year: 2022, Volume and Issue: 66(7), P. 831 - 847

Published: Nov. 9, 2022

Abstract The facts that many proteins with crucial biological functions do not have unique structures and processes are compartmentalized into the liquid-like biomolecular condensates, which formed via liquid–liquid phase separation (LLPS) surrounded by membrane, revolutionizing modern biology. These phenomena interlinked, as presence of intrinsic disorder represents an important requirement for a protein to undergo LLPS drives biogenesis numerous membrane-less organelles (MLOs). Therefore, one can consider these constituents new IDP–LLPS–MLO field. Furthermore, intrinsically disordered (IDPs), LLPS, MLOs represent clear link between molecular cellular biology soft matter condensed physics. Both IDP LLPS/MLO fields undergoing explosive development generate ever-increasing mountain data. data provide answers so long-standing questions it is difficult imagine in very recent past, scientists biologists operated without taking revolutionary concepts account. goal this essay deliver comprehensive review field but brief rather subjective outline some developments exciting fields.

Language: Английский

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The DNA damage response in the chromatin context: A coordinated process

Current Opinion in Cell Biology, Journal Year: 2023, Volume and Issue: 82, P. 102176 - 102176

Published: June 1, 2023

In the cell nucleus, DNA damage signaling and repair machineries operate on a chromatin substrate, integrity of which is critical for function viability. Here, we review recent advances in deciphering tight coordination between maintenance response (DDR). We discuss how DDR impacts marks, organization mobility, and, turn, alterations actively contribute to DDR, providing additional levels regulation. present our current knowledge molecular bases these processes physiological pathological conditions, also highlight open questions that emerge this expanding field.

Language: Английский

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Role of condensates in modulating DNA repair pathways and its implication for chemoresistance

Journal of Biological Chemistry, Journal Year: 2023, Volume and Issue: 299(6), P. 104800 - 104800

Published: May 9, 2023

For cells, it is important to repair DNA damage, such as double-strand and single-strand breaks, because unrepaired can compromise genetic integrity, potentially leading cell death or cancer. Cells have multiple damage pathways that been the subject of detailed genetic, biochemical, structural studies. Recently, scientific community has started gain evidence breaks may occur within biomolecular condensates also contribute through concentrating genotoxic agents used treat various cancers. Here, we summarize key features note where they implicated in breaks. We describe suggesting be involved other types including nucleotide modifications (e.g., mismatch oxidized bases), bulky lesions, among others. Finally, discuss old new mysteries could now addressed considering properties condensates, chemoresistance mechanisms. Chemical changes highly harmful living organisms. DNA, like molecules, undergo chemical reactions. 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Crosstalk histone response.Trends 19: 207-217Abstract (416) 72Yasuhara Zou Impacts compartmentalization repair.DNA 105103162Crossref (4) three main classes pathways. class single level non-distorting BER pathway. pathway repairs majority alkylating damages removal base. It (SSBs) PARP (73Caldecott K.W. break disease.Trends 32: 733-745Abstract 74Saville K.M. Clark Wilk Rogers G.D. Andrews Koczor al.NAD(+)-mediated mammalian 93102930Crossref 75Caldecott Mammalian dancing moonlight.DNA 93102921Crossref second includes NER pathway, repairing distorting deriving adducts UV-induced excising degrading stretch ssDNA containing then restoring correct nucleotides polymerization-dependent (76Apelt Lans Schärer O.D. Luijsterburg M.S. Nucleotide leaves mark chromatin: detection nucleosomes.Cell. 7925-7942Crossref (12) 77Duan Speer Ulibarri K.J. Mao Transcription-coupled insights approaches.DNA 103103126Crossref (11) 78Krasikova Rechkunova Lavrik Neurological Abnormalities.Int. 22: 6220Crossref third MMR, whose polymerase misincorporation errors ensuring highest fidelity process. MMR replacement strand 3). usually originate following: (i) mismatches occurring replication; (ii) minority G, (iii) bulges repeated oligonucleotide sequences, trinucleotide expansion (79Elez Mismatch preserving genome

Language: Английский

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Large-scale exome sequence analysis identifies sex- and age-specific determinants of obesity

Cell Genomics, Journal Year: 2023, Volume and Issue: 3(8), P. 100362 - 100362

Published: Aug. 1, 2023

Obesity contributes substantially to the global burden of disease and has a significant heritable component. Recent large-scale exome sequencing studies identified several genes in which rare, protein-coding variants have large effects on adult body mass index (BMI). Here we extended such work by performing sex-stratified associations UK Biobank study (N∼420,000). We rare heterozygous loss-of-function increases BMI women (DIDO1, PTPRG, SLC12A5) men (SLTM), with effect sizes up ∼8 kg/m2. This is complemented analyses implicating OBSCN MADD for recalled childhood adiposity. The known functions these genes, as well findings common variant genome-wide pathway enrichment analyses, suggest role neuron death, apoptosis, DNA damage response mechanisms susceptibility obesity across life-course. These highlight importance considering sex-specific life-course genetic regulation obesity.

Language: Английский

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Compartmentalization of the SUMO/RNF4 pathway by SLX4 drives DNA repair

Molecular Cell, Journal Year: 2023, Volume and Issue: 83(10), P. 1640 - 1658.e9

Published: April 13, 2023

Language: Английский

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Nuclear and genome dynamics underlying DNA double-strand break repair

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

Published: March 17, 2025

Language: Английский

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Histone H2A variants: Diversifying chromatin to ensure genome integrity

Seminars in Cell and Developmental Biology, Journal Year: 2022, Volume and Issue: 135, P. 59 - 72

Published: March 21, 2022

Language: Английский

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Liquid-liquid phase separation of nucleocapsid proteins during SARS-CoV-2 and HIV-1 replication

Cell Reports, Journal Year: 2022, Volume and Issue: 42(1), P. 111968 - 111968

Published: Dec. 26, 2022

The leap of retroviruses and coronaviruses from animal hosts to humans has led two ongoing pandemics tens millions deaths worldwide. Retrovirus coronavirus nucleocapsid proteins have been studied extensively as potential drug targets due their central roles in virus replication, among which is capacity bind respective genomic RNAs for packaging into nascent virions. This review focuses on fundamental studies these how intrinsic abilities condense through liquid-liquid phase separation (LLPS) contribute viral replication. Therapeutic targeting condensates methodological advances are also described address future questions contributes

Language: Английский

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