SUMO-Targeted Ubiquitin Ligases and Their Functions in Maintaining Genome Stability DOI Open Access
Ya‐Chu Chang, Marissa K. Oram, Anja‐Katrin Bielinsky

et al.

International Journal of Molecular Sciences, Journal Year: 2021, Volume and Issue: 22(10), P. 5391 - 5391

Published: May 20, 2021

Small ubiquitin-like modifier (SUMO)-targeted E3 ubiquitin ligases (STUbLs) are specialized enzymes that recognize SUMOylated proteins and attach to them. They therefore connect the cellular SUMOylation ubiquitination circuits. STUbLs participate in diverse molecular processes span cell cycle regulated events, including DNA repair, replication, mitosis, transcription. operate during unperturbed conditions response challenges, such as genotoxic stress. These modify their target substrates by catalyzing chains form different linkages, resulting proteolytic or non-proteolytic outcomes. Often, function compartmentalized environments, nuclear envelope kinetochore, actively aid relocalization of damaged stalled replication forks promote repair fork restart. Furthermore, reside same vicinity SUMO proteases deubiquitinases (DUBs), providing spatiotemporal control targets. In this review, we focus on mechanisms which help maintain genome stability across species.

Language: Английский

Heterochromatin-Driven Nuclear Softening Protects the Genome against Mechanical Stress-Induced Damage DOI Creative Commons
Michele M. Nava, Yekaterina A. Miroshnikova, Leah C. Biggs

et al.

Cell, Journal Year: 2020, Volume and Issue: 181(4), P. 800 - 817.e22

Published: April 16, 2020

Tissue homeostasis requires maintenance of functional integrity under stress. A central source stress is mechanical force that acts on cells, their nuclei, and chromatin, but how the genome protected against unclear. We show stretch deforms nucleus, which cells initially counteract via a calcium-dependent nuclear softening driven by loss H3K9me3-marked heterochromatin. The resulting changes in chromatin rheology architecture are required to insulate genetic material from force. Failure mount this mechanoresponse results DNA damage. Persistent, high-amplitude induces supracellular alignment tissue redistribute energy before it reaches nucleus. This tissue-scale mechanoadaptation functions through separate pathway mediated cell-cell contacts allows cells/tissues switch off mechanotransduction restore initial state. Our work identifies an unconventional role altering its own state maintain response deformation.

Language: Английский

Citations

476
Mechanics and functional consequences of nuclear deformations DOI
Yohalie Kalukula, Andrew D. Stephens, Jan Lammerding

et al.

Nature Reviews Molecular Cell Biology, Journal Year: 2022, Volume and Issue: 23(9), P. 583 - 602

Published: May 5, 2022

Language: Английский

Citations

270
Lamina-associated domains: peripheral matters and internal affairs DOI Creative Commons
Nolwenn Briand, Philippe Collas

Genome biology, Journal Year: 2020, Volume and Issue: 21(1)

Published: April 2, 2020

Abstract At the nuclear periphery, associations of chromatin with lamina through lamina-associated domains (LADs) aid functional organization genome. We review LADs and provide evidence LAD heterogeneity from cell ensemble single-cell data. are typically repressive environments in genome; nonetheless, we discuss findings lamin interactions regulatory elements active genes, role lamins may play genome regulation. address relationship between other organizers, involvement laminopathies. The current data lay basis for future studies on significance lamin-chromatin health disease.

Language: Английский

Citations

213
Homotypic clustering of L1 and B1/Alu repeats compartmentalizes the 3D genome DOI Creative Commons
Jiangbo Lu, Lei Chang, Tong Li

et al.

Cell Research, Journal Year: 2021, Volume and Issue: 31(6), P. 613 - 630

Published: Jan. 29, 2021

Organization of the genome into euchromatin and heterochromatin appears to be evolutionarily conserved relatively stable during lineage differentiation. In an effort unravel basic principle underlying folding, here we focus on itself report a fundamental role for L1 (LINE1 or LINE-1) B1/Alu retrotransposons, most abundant subclasses repetitive sequences, in chromatin compartmentalization. We find that homotypic clustering demarcates grossly exclusive domains, characterizes predicts Hi-C compartments. Spatial segregation L1-rich sequences nuclear nucleolar peripheries B1/Alu-rich interior is mouse human cells occurs dynamically cell cycle. addition, de novo establishment B1 coincident with formation higher-order structures early embryogenesis critically regulated by transcripts. Importantly, depletion transcripts embryonic stem drastically weakens repeat contacts compartmental strength, disrupts L1- B1-rich chromosomal at genome-wide individual sites. Mechanistically, co-localization liquid droplet DNA RNA protein HP1α suggest phase-separation mechanism which promotes Taken together, propose genetically encoded model repeats blueprint macrostructure. Our explains robustness folding common core, dynamic gene regulation overlaid across cells.

Language: Английский

Citations

159
Genomic Repeats Categorize Genes with Distinct Functions for Orchestrated Regulation DOI Creative Commons

Jiayun Lu,

Wen Shao, Lei Chang

et al.

Cell Reports, Journal Year: 2020, Volume and Issue: 30(10), P. 3296 - 3311.e5

Published: March 1, 2020

Repetitive elements are abundantly distributed in mammalian genomes. Here, we reveal a striking association between repeat subtypes and gene function. SINE, L1, low-complexity repeats demarcate distinct functional categories of genes may dictate the time level expression by providing binding sites for different regulatory proteins. Importantly, imaging sequencing analysis show that L1 sequester large set with specialized functions nucleolus- lamina-associated inactive domains depleted SINE repeats. In addition, transcripts bind extensively to its DNA embryonic stem cells (ESCs). Depletion RNA ESCs leads relocation L1-enriched chromosomal segments from nuclear interior de-repression L1-associated genes. These results demonstrate role silencing suggest general theme genomic orchestrating function, regulation, their host

Language: Английский

Citations

140
Long-range interactions between topologically associating domains shape the four-dimensional genome during differentiation DOI
Jonas Paulsen, Tharvesh M. Liyakat Ali, Maxim Nekrasov

et al.

Nature Genetics, Journal Year: 2019, Volume and Issue: 51(5), P. 835 - 843

Published: April 22, 2019

Language: Английский

Citations

128
H3K9me2 orchestrates inheritance of spatial positioning of peripheral heterochromatin through mitosis DOI Creative Commons
Andrey Poleshko, Cheryl L. Smith, Son C. Nguyen

et al.

eLife, Journal Year: 2019, Volume and Issue: 8

Published: Oct. 1, 2019

Cell-type-specific 3D organization of the genome is unrecognizable during mitosis. It remains unclear how essential positional information transmitted through cell division such that a daughter recapitulates spatial parent. Lamina-associated domains (LADs) are regions repressive heterochromatin positioned at nuclear periphery vary by type and contribute to cell-specific gene expression identity. Here we show histone 3 lysine 9 dimethylation (H3K9me2) an evolutionarily conserved, specific mark peripheral it retained During mitosis, phosphorylation serine 10 temporarily shields H3K9me2 allowing for dissociation chromatin from lamina. Using high-resolution immuno-oligoFISH, demonstrate H3K9me2-enriched genomic regions, which lamina in interphase cells prior re-associate with forming before mitotic exit. The modification ensures safeguarded individual LADs re-established nuclei. Thus, acts as architectural guidepost. Our data establish mechanism epigenetic memory inheritance genome.

Language: Английский

Citations

105
Suppression of liquid–liquid phase separation by 1,6-hexanediol partially compromises the 3D genome organization in living cells DOI Creative Commons
Sergey V. Ulianov,

Artem K. Velichko,

Mikhail Magnitov

et al.

Nucleic Acids Research, Journal Year: 2021, Volume and Issue: 49(18), P. 10524 - 10541

Published: March 26, 2021

Abstract Liquid–liquid phase separation (LLPS) contributes to the spatial and functional segregation of molecular processes within cell nucleus. However, role played by LLPS in chromatin folding living cells remains unclear. Here, using stochastic optical reconstruction microscopy (STORM) Hi-C techniques, we studied effects 1,6-hexanediol (1,6-HD)-mediated disruption/modulation on higher-order organization cells. We found that 1,6-HD treatment caused enlargement nucleosome clutches their more uniform distribution nuclear space. At a megabase-scale, underwent moderate but irreversible perturbations resulted partial mixing A B compartments. The removal from culture medium did not allow acquire initial configurations, compact repressed than untreated also weakened enhancer-promoter interactions TAD insulation considerably affect CTCF-dependent loops. Our results suggest 1,6-HD-sensitive plays limited constraining its patterns facilitating compartmentalization at different levels.

Language: Английский

Citations

93
Core Components of the Nuclear Pore Bind Distinct States of Chromatin and Contribute to Polycomb Repression DOI Creative Commons

Alejandro Gozalo,

Ashley Duke,

Yemin Lan

et al.

Molecular Cell, Journal Year: 2019, Volume and Issue: 77(1), P. 67 - 81.e7

Published: Nov. 26, 2019

Language: Английский

Citations

88
Single-nucleus transcriptomic landscape of primate hippocampal aging DOI Creative Commons
Hui Zhang, Jiaming Li, Jie Ren

et al.

Protein & Cell, Journal Year: 2021, Volume and Issue: 12(9), P. 695 - 716

Published: May 30, 2021

The hippocampus plays a crucial role in learning and memory, its progressive deterioration with age is functionally linked to variety of human neurodegenerative diseases. Yet systematic profiling the aging effects on various hippocampal cell types primates still missing. Here, we reported new aging-associated phenotypic changes primate hippocampus. These include, particular, increased DNA damage heterochromatin erosion time, alongside loss proteostasis elevated inflammation. To understand their cellular molecular causes, established first single-nucleus transcriptomic atlas aging. Among 12 identified types, neural transiently amplifying progenitor (TAPC) microglia were most affected by In-depth dissection gene-expression dynamics revealed impaired TAPC division compromised neuronal function along neurogenesis trajectory; additionally pro-inflammatory responses aged oligodendrocyte, as well dysregulated coagulation pathways endothelial cells may contribute hostile microenvironment for neurogenesis. This rich resource understanding provide potential diagnostic biomarkers therapeutic interventions against age-related

Language: Английский

Citations

86