Synthetic Lethality between Cohesin and WNT Signaling Pathways in Diverse Cancer Contexts DOI Creative Commons
Maria Michela Pallotta, Maddalena Di Nardo, Antonio Musio

et al.

Cells, Journal Year: 2024, Volume and Issue: 13(7), P. 608 - 608

Published: March 30, 2024

Cohesin is a highly conserved ring-shaped complex involved in topologically embracing chromatids, gene expression regulation, genome compartmentalization, and stability maintenance. Genomic analyses have detected mutations the cohesin wide array of human tumors. These findings led to increased interest as potential target cancer therapy. Synthetic lethality has been suggested an approach exploit genetic differences cells influence their selective killing. In this study, we show that ESCO1, NIPBL, PDS5B, RAD21, SMC1A, SMC3, STAG2, WAPL genes are synthetically lethal with stimulation WNT signaling obtained following LY2090314 treatment, GSK3 inhibitor, several cell lines. Moreover, treatment stabilization β-catenin affected c-MYC, probably due occupancy decrease at c-MYC promoter. Finally, caused dysregulation mainly involving pathways related transcription proliferation, chromatin remodeling. For first time, our work provides underlying molecular basis for synthetic suggests targeting may be promising therapeutic tumors carrying mutated cohesin.

Language: Английский

Integrated multi-omics analyses identify anti-viral host factors and pathways controlling SARS-CoV-2 infection DOI Creative Commons
Jiakai Hou, Yanjun Wei, Jing Zou

et al.

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: Jan. 2, 2024

Host anti-viral factors are essential for controlling SARS-CoV-2 infection but remain largely unknown due to the biases of previous large-scale studies toward pro-viral host factors. To fill in this knowledge gap, we perform a genome-wide CRISPR dropout screen and integrate analyses multi-omics data screen, association studies, single-cell RNA-Seq, host-virus proteins or protein/RNA interactome. This study uncovers many that currently underappreciated, including components V-ATPases, ESCRT, N-glycosylation pathways modulate viral entry and/or replication. The cohesin complex is also identified as an pathway, suggesting important role three-dimensional chromatin organization mediating host-viral interaction. Furthermore, discover another regulator KLF5, transcriptional factor involved sphingolipid metabolism, which up-regulated, harbors genetic variations linked COVID-19 patients with severe symptoms. Anti-viral effects three candidates (DAZAP2/VTA1/KLF5) confirmed individually. Molecular characterization DAZAP2/VTA1/KLF5-knockout cells highlights involvement genes related coagulation system determining severity COVID-19. Together, our results provide further resources understanding network during may help develop new countermeasure strategies.

Language: Английский

Citations

20
Rules of engagement for condensins and cohesins guide mitotic chromosome formation DOI Creative Commons
Kumiko Samejima, Johan H. Gibcus, Sameer Abraham

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: April 18, 2024

Abstract During mitosis, interphase chromatin is rapidly converted into rod-shaped mitotic chromosomes. Using Hi-C, imaging, proteomics and polymer modeling, we determine how the activity interplay between loop-extruding SMC motors accomplishes this dramatic transition. Our work reveals rules of engagement for complexes that are critical allowing cells to refold We find condensin disassembles loop organization by evicting or displacing extrusive cohesin. In contrast, bypasses cohesive cohesins, thereby maintaining sister chromatid cohesion while separating sisters. Studies chromosomes formed cohesin, II I alone in combination allow us develop new models chromosome conformation. these models, loops consecutive not overlapping, implying condensins do freely pass one another but stall upon encountering each other. The dynamics Hi-C interactions morphology reveal during prophase extruded vivo at ∼1-3 kb/sec as they form a disordered discontinuous helical scaffold within individual chromatids.

Language: Английский

Citations

18
The multi-functional Smc5/6 complex in genome protection and disease DOI
Xiao Peng, Xiaolan Zhao

Nature Structural & Molecular Biology, Journal Year: 2023, Volume and Issue: 30(6), P. 724 - 734

Published: June 1, 2023

Language: Английский

Citations

29
The chromosome folding problem and how cells solve it DOI Creative Commons
Job Dekker, Leonid A. Mirny

Cell, Journal Year: 2024, Volume and Issue: 187(23), P. 6424 - 6450

Published: Nov. 1, 2024

Every cell must solve the problem of how to fold its genome. We describe folded state chromosomes is result combined activity multiple conserved mechanisms. Homotypic affinity-driven interactions lead spatial partitioning active and inactive loci. Molecular motors through loop extrusion. Topological features such as supercoiling entanglements contribute chromosome folding dynamics, tethering loci sub-nuclear structures adds additional constraints. Dramatically diverse conformations observed throughout cycle across tree life can be explained differential regulation implementation these basic propose that first functions are mediate genome replication, compaction, segregation mechanisms have subsequently been co-opted for other roles, including long-range gene regulation, in different conditions, types, species.

Language: Английский

Citations

10
The SMC5/6 complex: folding chromosomes back into shape when genomes take a break DOI Creative Commons
Shamayita Roy, Hemanta Adhikary, Damien D’Amours

et al.

Nucleic Acids Research, Journal Year: 2024, Volume and Issue: 52(5), P. 2112 - 2129

Published: Feb. 2, 2024

Abstract High-level folding of chromatin is a key determinant the shape and functional state chromosomes. During cell division, structural maintenance chromosome (SMC) complexes such as condensin cohesin ensure large-scale into visible In contrast, SMC5/6 complex plays more local context-specific roles in organization interphase chromosomes with important implications for health disease. Recent advances single-molecule biophysics cryo-electron microscopy revealed insights architecture how interactions connecting to components give rise its unique repertoire functions. this review, we provide an integrative view features that differentiates from other SMC enzymes these enable dramatic reorganization DNA space during repair reactions genome transactions. Finally, explore mechanistic basis dynamic targeting damaged crucial role human health.

Language: Английский

Citations

9
Extensive mutual influences of SMC complexes shape 3D genome folding DOI
Han Zhao, Lirong Shu, Shiyi Qin

et al.

Nature, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 26, 2025

Language: Английский

Citations

1
SRBD1, a highly conserved gene required for chromosome individualization DOI
Jonne A. Raaijmakers, Louise M.E. Janssen, Abdelghani Mazouzi

et al.

Cell Reports, Journal Year: 2025, Volume and Issue: 44(4), P. 115443 - 115443

Published: March 18, 2025

Language: Английский

Citations

1
An integrated view of the structure and function of the human 4D nucleome DOI Creative Commons
Job Dekker,

Betul Akgol Oksuz,

Yang Zhang

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Sept. 19, 2024

Abstract The dynamic three-dimensional (3D) organization of the human genome (the “4D Nucleome”) is closely linked to function. Here, we integrate a wide variety genomic data generated by 4D Nucleome Project provide detailed view 3D in widely used embryonic stem cells (H1-hESCs) and immortalized fibroblasts (HFFc6). We extensive benchmarking mapping assays these diverse datasets annotate spatial features across scales. reveal rich complexity chromatin domains their sub-nuclear positions, over one hundred thousand structural loops promoter-enhancer interactions. developed models population-based individual cell-to-cell variation structure, establishing connections between chromosome folding, nuclear organization, looping, gene transcription, DNA replication. demonstrate use computational methods predict folding from sequence, uncovering potential effects genetic variants on structure Together, this comprehensive analysis contributes insights into enhances our understanding regulation function general.

Language: Английский

Citations

7
Loop extrusion-mediated plasmid DNA cleavage by the bacterial SMC Wadjet complex DOI
Biswajit Pradhan, Amar Deep,

Jessica König

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Feb. 17, 2024

Structural maintenance of chromosomes (SMC) protein complexes play pivotal roles in genome organization and across all domains life. In prokaryotes, SMC family Wadjet structurally resemble the widespread MukBEF genome-organizing but serve a defensive role by inhibiting plasmid transformation. We previously showed that specifically cleaves circular DNA; however, molecular mechanism underlying DNA substrate recognition remains unclear. Here, we use vitro single-molecule imaging to directly visualize loop extrusion cleavage Wadjet. find is symmetric extruder simultaneously reels from both sides growing this activity requires dimeric JetABC supercomplex containing two dimers JetC motor subunit. On surface-anchored DNAs, extrudes full length 44 kilobase pair plasmid, stalls, then DNA. Our findings reveal specific elimination plasmids Wadjet, establish as an evolutionarily conserved among kingdoms

Language: Английский

Citations

6
Loop-extrusion-mediated plasmid DNA cleavage by the bacterial SMC Wadjet complex DOI Creative Commons
Biswajit Pradhan, Amar Deep,

Jessica König

et al.

Molecular Cell, Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 1, 2024

Structural maintenance of chromosomes (SMC) complexes play pivotal roles in genome organization and across all domains life. In prokaryotes, SMC-family Wadjet structurally resemble the widespread MukBEF but serve a defensive role by inhibiting plasmid transformation. We previously showed that specifically cleaves DNA; however, molecular mechanism underlying recognition remains unclear. Here, we use vitro single-molecule imaging to directly visualize DNA loop extrusion cleavage Wadjet. find is symmetric extruder simultaneously reels from both sides this activity requires dimeric JetABC supercomplex. On surface-anchored DNAs, extrudes full length 44-kb-pair plasmid, stalls, DNA. Our findings reveal specific elimination plasmids establish as an evolutionarily conserved among SMC kingdoms

Language: Английский

Citations

6