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      Chromosome architecture and homologous recombination in meiosis

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          Abstract

          Meiocytes organize higher-order chromosome structures comprising arrays of chromatin loops organized at their bases by linear axes. As meiotic prophase progresses, the axes of homologous chromosomes align and synapse along their lengths to form ladder-like structures called synaptonemal complexes (SCs). The entire process of meiotic recombination, from initiation via programmed DNA double-strand breaks (DSBs) to completion of DSB repair with crossover or non-crossover outcomes, occurs in the context of chromosome axes and SCs. These meiosis-specific chromosome structures provide specialized environments for the regulation of DSB formation and crossing over. In this review, we summarize insights into the importance of chromosome architecture in the regulation of meiotic recombination, focusing on cohesin-mediated axis formation, DSB regulation via tethered loop-axis complexes, inter-homolog template bias facilitated by axial proteins, and crossover regulation in the context of the SCs. We also discuss emerging evidence that the SUMO and the ubiquitin-proteasome system function in the organization of chromosome structure and regulation of meiotic recombination.

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          Most cited references175

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          DNA loop extrusion by human cohesin

          Eukaryotic genomes are folded into loops and topologically-associating domains (TADs), which contribute to chromatin structure, gene regulation and recombination. These structures depend on cohesin, a ring-shaped DNA-entrapping ATPase complex which has been proposed to form loops by extrusion. Such an activity has been observed for condensin, which forms loops in mitosis, but not for cohesin. Here we show, using biochemical reconstitution, that single human cohesin complexes form DNA loops symmetrically at up to 2.1 kbp per second. Loop formation and maintenance depend on cohesin’s ATPase activity and on NIPBL-MAU2, but not on topological entrapment of DNA by cohesin. During loop formation, cohesin and NIPBL-MAU2 reside at the base of loops, indicating that they generate loops by extrusion. Our results show that cohesin and NIPBL-MAU2 form an active holo-enzyme that interacts with DNA either pseudo-topologically or non-topologically to extrude genomic interphase DNA into loops.
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            Human cohesin compacts DNA by loop extrusion

            Cohesin is a chromosome-bound multisubunit ATPase complex. Following its loading onto chromosomes, cohesin generates chromosome loops to regulate chromosome functions. It has been suggested that cohesin organizes the genome via loop extrusion, but direct evidence is lacking. Here, we use single-molecule imaging to show that recombinant human cohesin-NIPBL complex compacts both naked and nucleosome-bound DNA by extruding DNA loops. DNA compaction by cohesin requires ATP hydrolysis, and is force-sensitive. This compaction is processive over tens of kilobases (kb) at an average rate of 0.5 kb per second. Compaction of double-tethered DNA suggests that a cohesin dimer extrudes DNA loops bidirectionally. Our results establish cohesin-NIPBL as an ATP-driven molecular machine capable of loop extrusion.
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              Topologically associating domains and chromatin loops depend on cohesin and are regulated by CTCF, WAPL, and PDS5 proteins

              Mammalian genomes are spatially organized into compartments, topologically associating domains (TADs), and loops to facilitate gene regulation and other chromosomal functions. How compartments, TADs, and loops are generated is unknown. It has been proposed that cohesin forms TADs and loops by extruding chromatin loops until it encounters CTCF, but direct evidence for this hypothesis is missing. Here, we show that cohesin suppresses compartments but is required for TADs and loops, that CTCF defines their boundaries, and that the cohesin unloading factor WAPL and its PDS5 binding partners control the length of loops. In the absence of WAPL and PDS5 proteins, cohesin forms extended loops, presumably by passing CTCF sites, accumulates in axial chromosomal positions (vermicelli), and condenses chromosomes. Unexpectedly, PDS5 proteins are also required for boundary function. These results show that cohesin has an essential genome‐wide function in mediating long‐range chromatin interactions and support the hypothesis that cohesin creates these by loop extrusion, until it is delayed by CTCF in a manner dependent on PDS5 proteins, or until it is released from DNA by WAPL.
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                Author and article information

                Contributors
                Journal
                Front Cell Dev Biol
                Front Cell Dev Biol
                Front. Cell Dev. Biol.
                Frontiers in Cell and Developmental Biology
                Frontiers Media S.A.
                2296-634X
                06 January 2023
                2022
                : 10
                : 1097446
                Affiliations
                Institute for Protein Research , Osaka University , Suita, Osaka, Japan
                Author notes

                Edited by: Ricardo Benavente, Julius Maximilian University of Würzburg, Germany

                Reviewed by: Kevin Corbett, University of California, San Diego, United States

                Alyssa Rodriguez, University of California, San Diego, in collaboration with reviewer KC

                Rocio Gomez, Autonomous University of Madrid, Spain

                This article was submitted to Nuclear Organization and Dynamics, a section of the journal Frontiers in Cell and Developmental Biology

                Article
                1097446
                10.3389/fcell.2022.1097446
                9853400
                36684419
                7c791f3e-dbdf-4fb6-8284-9fc258cac5e0
                Copyright © 2023 Ito and Shinohara.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 13 November 2022
                : 22 December 2022
                Categories
                Cell and Developmental Biology
                Review

                cohesin,axis-loop structure,synaptonemal complex,meiotic recombination,crossover

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