scholarly journals Chromosome Folding Promotes Intrachromosomal Aberrations under Radiation- and Nuclease-Induced DNA Breakage

2021 ◽  
Vol 22 (22) ◽  
pp. 12186
Author(s):  
Yuri Eidelman ◽  
Ilya Salnikov ◽  
Svetlana Slanina ◽  
Sergey Andreev
Keyword(s):  
Chromosomal Aberrations ◽  
Physical Modeling ◽  
Cancer Biology ◽  
Chromosome Structure ◽  
Joint Analysis ◽  
Chromosome Organization ◽  
Dna Double Strand Breaks ◽  
Chromosome Conformation ◽  
Structure Heterogeneity ◽  
Translocation Breakpoints

The long-standing question in radiation and cancer biology is how principles of chromosome organization impact the formation of chromosomal aberrations (CAs). To address this issue, we developed a physical modeling approach and analyzed high-throughput genomic data from chromosome conformation capture (Hi-C) and translocation sequencing (HTGTS) methods. Combining modeling of chromosome structure and of chromosomal aberrations induced by ionizing radiation (IR) and nuclease we made predictions which quantitatively correlated with key experimental findings in mouse chromosomes: chromosome contact maps, high frequency of cis-translocation breakpoints far outside of the site of nuclease-induced DNA double-strand breaks (DSBs), the distinct shape of breakpoint distribution in chromosomes with different 3D organizations. These correlations support the heteropolymer globule principle of chromosome organization in G1-arrested pro-B mouse cells. The joint analysis of Hi-C, HTGTS and physical modeling data offers mechanistic insight into how chromosome structure heterogeneity, globular folding and lesion dynamics drive IR-recurrent CAs. The results provide the biophysical and computational basis for the analysis of chromosome aberration landscape under IR and nuclease-induced DSBs.

scholarly journals DNA-dependent macromolecular condensation drives self-assembly of the meiotic DNA break machinery

2020 ◽  
Author(s):  
Corentin Claeys Bouuaert ◽  
Stephen Pu ◽  
Juncheng Wang ◽  
Dinshaw J. Patel ◽  
Scott Keeney
Keyword(s):  
Self Assembly ◽  
Chromosome Structure ◽  
Coiled Coil ◽  
Double Strand Breaks ◽  
Dna Double Strand Breaks ◽  
Strand Breaks ◽  
Dna Breakage ◽  
And Control

Formation of meiotic DNA double-strand breaks (DSBs) by Spo11 is tightly regulated and tied to chromosome structure, but the higher-order assemblies that execute and control DNA breakage are poorly understood. We address this question through molecular characterization of Saccharomyces cerevisiae RMM proteins (Rec114, Mei4 and Mer2)—essential, conserved components of the DSB machinery. Each subcomplex of Rec114–Mei4 (2:1 heterotrimer) or Mer2 (homotetrameric coiled coil) is monodisperse in solution, but they independently condense with DNA into dynamic, reversible nucleoprotein clusters that share properties with phase-separated systems. Multivalent interactions drive condensation, which correlates with DSB formation in vivo. Condensates fuse into mixed Rec114–Mei4–Mer2 clusters that further recruit Spo11 complexes. Our data show how the DSB machinery self-assembles on chromosome axes to create centers of DSB activity. We propose that multilayered control of Spo11 arises from recruitment of regulatory components and modulation of biophysical properties of the condensates.

scholarly journals Chromosome remodelling by SMC/Condensin in B. subtilis is regulated by Soj/ParA during growth and sporulation

2021 ◽  
Author(s):  
David M Roberts ◽  
Anna Anchimiuk ◽  
Tomas G Kloosterman ◽  
Heath Murray ◽  
Ling Juan Wu ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Bacillus Subtilis ◽  
Chromosome Segregation ◽  
Chromosome Structure ◽  
Replication Initiation ◽  
Chromosome Organization ◽  
Filament Formation ◽  
Axial Filament ◽  
Dna Replication Initiation ◽  
The Web

SMC complexes, loaded at ParB-parS sites, are key mediators of chromosome organization in bacteria. ParA/Soj proteins interact with ParB/Spo0J in a pathway involving ATP-dependent dimerization and DNA binding, leading to chromosome segregation and SMC loading. In Bacillus subtilis, ParA/Soj also regulates DNA replication initiation, and along with ParB/Spo0J is involved in cell cycle changes during endospore formation. The first morphological stage in sporulation is the formation of an elongated chromosome structure called an axial filament. We now show that a major redistribution of SMC complexes drives axial filament formation, in a process regulated by ParA/Soj. Unexpectedly, this regulation is dependent on monomeric forms of ParA/Soj that cannot bind DNA or hydrolyse ATP. These results reveal a new role for ParA/Soj proteins in the regulation of SMC dynamics in bacteria, and yet further complexity in the web of interactions involving chromosome replication, segregation, and organization, controlled by ParAB and SMC.

scholarly journals Loop extrusion as a mechanism for DNA Double-Strand Breaks repair foci formation

2020 ◽  
Author(s):  
Coline Arnould ◽  
Vincent Rocher ◽  
Thomas Clouaire ◽  
Pierre Caron ◽  
Philippe. E. Mangeot ◽  
...  
Keyword(s):  
Chromatin Modification ◽  
Double Strand Breaks ◽  
Genome Integrity ◽  
Dna Double Strand Breaks ◽  
Chromatin Domains ◽  
Chromosome Conformation ◽  
Strand Breaks ◽  
3D Genome ◽  
Damage Response ◽  
Transcription And Replication

DNA Double-Strand Breaks (DSBs) repair is essential to safeguard genome integrity. Upon DSBs, the ATM PI3K kinase rapidly triggers the establishment of megabase-sized, γH2AX-decorated chromatin domains which further act as seeds for the formation of DNA Damage Response (DDR) foci1. How these foci are rapidly assembled in order to establish a “repair-prone” environment within the nucleus is yet unclear. Topologically Associating Domains (TADs) are a key feature of 3D genome organization that regulate transcription and replication, but little is known about their contribution to DNA repair processes2,3. Here we found that TADs are functional units of the DDR, instrumental for the correct establishment of γH2AX/53BP1 chromatin domains in a manner that involves one-sided cohesin-mediated loop extrusion on both sides of the DSB. We propose a model whereby H2AX-containing nucleosomes are rapidly phosphorylated as they actively pass by DSB-anchored cohesin. Our work highlights the critical impact of chromosome conformation in the maintenance of genome integrity and provides the first example of a chromatin modification established by loop extrusion.

scholarly journals Wapl releases Scc1-cohesin and regulates chromosome structure and segregation in mouse oocytes

2020 ◽  
Vol 219 (4) ◽  
Author(s):  
Mariana C.C. Silva ◽  
Sean Powell ◽  
Sabrina Ladstätter ◽  
Johanna Gassler ◽  
Roman Stocsits ◽  
...  
Keyword(s):  
Residence Time ◽  
Chromosome Segregation ◽  
Chromosome Structure ◽  
Somatic Cells ◽  
Cell Types ◽  
Chromosome Organization ◽  
Loop Size ◽  
Mouse Oocytes ◽  
Single Nucleus ◽  
Meiosis I

Cohesin is essential for genome folding and inheritance. In somatic cells, these functions are both mediated by Scc1-cohesin, which in mitosis is released from chromosomes by Wapl and separase. In mammalian oocytes, cohesion is mediated by Rec8-cohesin. Scc1 is expressed but neither required nor sufficient for cohesion, and its function remains unknown. Likewise, it is unknown whether Wapl regulates one or both cohesin complexes and chromosome segregation in mature oocytes. Here, we show that Wapl is required for accurate meiosis I chromosome segregation, predominantly releases Scc1-cohesin from chromosomes, and promotes production of euploid eggs. Using single-nucleus Hi-C, we found that Scc1 is essential for chromosome organization in oocytes. Increasing Scc1 residence time on chromosomes by Wapl depletion leads to vermicelli formation and intra-loop structures but, unlike in somatic cells, does not increase loop size. We conclude that distinct cohesin complexes generate loops and cohesion in oocytes and propose that the same principle applies to all cell types and species.

Reversible Changes of Chromosome Structure upon Different Concentrations of Divalent Cations

2019 ◽  
Vol 25 (3) ◽  
pp. 817-821 ◽  
Author(s):  
Astari Dwiranti ◽  
Hideaki Takata ◽  
Kiichi Fukui
Keyword(s):  
Electron Microscopy ◽  
Chromosome Structure ◽  
Ethylenediaminetetraacetic Acid ◽  
Divalent Cations ◽  
Chromosome Organization ◽  
Human Chromosomes ◽  
Tetraacetic Acid ◽  
Structural Details ◽  
Scanning Electron

AbstractThe structural details of chromosomes have been of interest to researchers for many years, but how the metaphase chromosome is constructed remains unsolved. Divalent cations have been suggested to be required for the organization of chromosomes. However, detailed information about the role of these cations in chromosome organization is still limited. In the current study, we investigated the effects of Ca2+ and Mg2+ depletion and the reversibility upon re-addition of one of the two ions. Human chromosomes were treated with different concentrations of Ca2+and Mg2+. Depletion of Ca2+ and both Ca2+ and Mg2+ were carried out using 1, 2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid and ethylenediaminetetraacetic acid (EDTA), respectively. Chromosome structure was examined by fluorescence microscopy and scanning electron microscopy. The results indicated that chromosome structures after treatment with a buffer without Mg2+, after Ca2+ depletion, as well as after depletion of both Mg2+, and Ca2+, yielded fewer compact structures with fibrous chromatin than those without cation depletion. Interestingly, the chromatin of EDTA-treated chromosomes reversed to their original granular diameters after re-addition of either Mg2+ or Ca2+ only. These findings signify the importance of divalent cations on the chromosome structure and suggest the interchangeable role of Ca2+ and Mg2+.

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