Contributions of transcriptional noise to leukaemia evolution: KAT2A as a case-study DOI Creative Commons
Cristina Pina

Philosophical Transactions of the Royal Society B Biological Sciences, Год журнала: 2024, Номер 379(1900)

Опубликована: Март 4, 2024

Transcriptional noise is proposed to participate in cell fate changes, but contributions mammalian differentiation systems, including cancer, remain associative. Cancer evolution driven by genetic variability, with modulatory or contributory participation of epigenetic variants. Accumulation variants enhances transcriptional noise, which can facilitate cancer transitions. Acute myeloid leukaemia (AML) an aggressive strong dependencies, characterized blocked differentiation. It constitutes attractive model probe links between and malignant regulation. Gcn5/KAT2A a classical regulator. Its loss increases modifies fates stem AML cells. By reviewing the analysis KAT2A-depleted pre-leukaemia models, I discuss that net result diversification secondary alternative programmes. Cellular enable hinder progression, respectively, types responsive mutations, maladaptation KAT2A-dependent noise-responsive genes ribosome biogenesis KAT2A destabilizes translational activity. putative perturbed translation biology, propose as for mechanistic integration control decisions. This article part discussion meeting issue ‘Causes consequences stochastic processes development disease’.

Язык: 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

и другие.

Nature Communications, Год журнала: 2024, Номер 15(1)

Опубликована: Янв. 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.

Язык: Английский

Процитировано

19
Rules of engagement for condensins and cohesins guide mitotic chromosome formation DOI Creative Commons
Kumiko Samejima, Johan H. Gibcus, Sameer Abraham

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Апрель 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.

Язык: Английский

Процитировано

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

Nature Structural & Molecular Biology, Год журнала: 2023, Номер 30(6), С. 724 - 734

Опубликована: Июнь 1, 2023

Язык: Английский

Процитировано

28
The SMC5/6 complex: folding chromosomes back into shape when genomes take a break DOI Creative Commons
Shamayita Roy, Hemanta Adhikary, Damien D’Amours

и другие.

Nucleic Acids Research, Год журнала: 2024, Номер 52(5), С. 2112 - 2129

Опубликована: Фев. 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.

Язык: Английский

Процитировано

9
The chromosome folding problem and how cells solve it DOI Creative Commons
Job Dekker, Leonid A. Mirny

Cell, Год журнала: 2024, Номер 187(23), С. 6424 - 6450

Опубликована: Ноя. 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.

Язык: Английский

Процитировано

9
Loop extrusion-mediated plasmid DNA cleavage by the bacterial SMC Wadjet complex DOI
Biswajit Pradhan, Amar Deep,

Jessica König

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Фев. 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

Язык: Английский

Процитировано

6
Condensin II activation by M18BP1 DOI Creative Commons
Alessandro Borsellini, Duccio Conti, Erin Cutts

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Май 3, 2024

ABSTRACT Condensin complexes promote the drastic spatial rearrangement of genome upon mitotic entry. II initiates chromosome condensation in early mitosis. To prevent during interphase, condensin is inhibited by MCPH1, but mechanism unknown. Through genetic and proteomic approaches, we identify M18BP1, a protein previously associated with centromere identity, as factor required for localization to chromatin. M18BP1 directly binds II’s CAP-G2 subunit competes MCPH1 binding. Upon entry, CDK1 mediated phosphorylation may switch from binding activate II. Our results fundamental evolutionarily conserved activation.

Язык: Английский

Процитировано

5
Loop-extrusion-mediated plasmid DNA cleavage by the bacterial SMC Wadjet complex DOI Creative Commons
Biswajit Pradhan, Amar Deep,

Jessica König

и другие.

Molecular Cell, Год журнала: 2024, Номер unknown

Опубликована: Дек. 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

Язык: Английский

Процитировано

5
Recombinant cyclin B-Cdk1-Suc1 capable of multi-site mitotic phosphorylation in vitro DOI Creative Commons
Keishi Shintomi,

Yuki Masahara-Negishi,

Masami Shima

и другие.

PLoS ONE, Год журнала: 2024, Номер 19(3), С. e0299003 - e0299003

Опубликована: Март 25, 2024

Cyclin-dependent kinase 1 (Cdk1) complexed with cyclin B phosphorylates multiple sites on hundreds of proteins during mitosis. However, it is not fully understood how multi-site mitotic phosphorylation by B-Cdk1 controls the structures and functions individual substrates. Here we develop an easy-to-use protocol to express recombinant vertebrate Cdk1 in insect cells from a single baculovirus vector purify their complexes excellent homogeneity. A series in-vitro assays demonstrate that can efficiently specifically phosphorylate SP TP motifs The addition Suc1 (a Cks1 homolog fission yeast) accelerates artificial substrate containing motifs. Importantly, show mitosis-specific multi-subunit condensin I complex be recapitulated vitro using B-Cdk1-Suc1. materials protocols described here will pave way for dissecting biochemical basis critical processes accompany Cdk1-mediated large-scale phosphorylation.

Язык: Английский

Процитировано

4
Sister chromatid cohesion through the lens of biochemical experiments DOI
Yasuto Murayama

Current Opinion in Cell Biology, Год журнала: 2025, Номер 93, С. 102464 - 102464

Опубликована: Янв. 28, 2025

Язык: Английский

Процитировано

0