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      Homologous chromosomes are stably conjoined for Drosophila male meiosis I by SUM, a multimerized protein assembly with modules for DNA-binding and for separase-mediated dissociation co-opted from cohesin

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          Abstract

          For meiosis I, homologous chromosomes must be paired into bivalents. Maintenance of homolog conjunction in bivalents until anaphase I depends on crossovers in canonical meiosis. However, instead of crossovers, an alternative system achieves homolog conjunction during the achiasmate male meiosis of Drosophila melanogaster. The proteins SNM, UNO and MNM are likely constituents of a physical linkage that conjoins homologs in D. melanogaster spermatocytes. Here, we report that SNM binds tightly to the C-terminal region of UNO. This interaction is homologous to that of the cohesin subunits stromalin/Scc3/STAG and α-kleisin, as revealed by sequence similarities, structure modeling and cross-link mass spectrometry. Importantly, purified SU_C, the heterodimeric complex of SNM and the C-terminal region of UNO, displayed DNA-binding in vitro. DNA-binding was severely impaired by mutational elimination of positively charged residues from the C-terminal helix of UNO. Phenotypic analyses in flies fully confirmed the physiological relevance of this basic helix for chromosome-binding and homolog conjunction during male meiosis. Beyond DNA, SU_C also bound MNM, one of many isoforms expressed from the complex mod(mdg4) locus. This binding of MNM to SU_C was mediated by the MNM-specific C-terminal region, while the purified N-terminal part common to all Mod(mdg4) isoforms multimerized into hexamers in vitro. Similarly, the UNO N-terminal domain formed tetramers in vitro. Thus, we suggest that multimerization confers to SUM, the assemblies composed of SNM, UNO and MNM, the capacity to conjoin homologous chromosomes stably by the resultant multivalent DNA-binding. Moreover, to permit homolog separation during anaphase I, SUM is dissociated by separase, since UNO, the α-kleisin-related protein, includes a separase cleavage site. In support of this proposal, we demonstrate that UNO cleavage by tobacco etch virus protease is sufficient to release homolog conjunction in vivo after mutational exchange of the separase cleavage site with that of the bio-orthogonal protease.

          Author summary

          A major purpose of meiosis is the reduction of genome ploidy from diploid to haploid. Therefore, homologous chromosomes are paired into bivalents before the first meiotic division. Conjunction of homologs into bivalents usually results from crossovers (generated by meiotic recombination) in combination with sister chromatid cohesion by cohesin complexes that preclude crossover terminalization. Cohesin is thought to form a proteinaceous ring around sister chromatids. After bivalent biorientation in the spindle, a particular cohesin subunit is cleaved by the endoprotease separase, allowing homolog separation during the first meiotic division. Surprisingly, homolog conjunction during meiosis in males of the fly Drosophila melanogaster does not involve crossover formation. Instead, an alternative homolog conjunction system is used. Here we report how the proteins of this alternative system form assemblies that bind DNA. Conjunction of homologous chromosomes in D. melanogaster males depends on these protein assemblies, functioning apparently akin to conventional glue rather than as topological embrace like cohesin. However, after bivalent biorientation, separase can be used nevertheless for efficient dissolution of the alternative homolog glue in D. melanogaster spermatocytes, as some of the alternative conjunction proteins have evolved from cohesin subunits.

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          Most cited references77

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          Highly accurate protein structure prediction with AlphaFold

          Proteins are essential to life, and understanding their structure can facilitate a mechanistic understanding of their function. Through an enormous experimental effort 1 – 4 , the structures of around 100,000 unique proteins have been determined 5 , but this represents a small fraction of the billions of known protein sequences 6 , 7 . Structural coverage is bottlenecked by the months to years of painstaking effort required to determine a single protein structure. Accurate computational approaches are needed to address this gap and to enable large-scale structural bioinformatics. Predicting the three-dimensional structure that a protein will adopt based solely on its amino acid sequence—the structure prediction component of the ‘protein folding problem’ 8 —has been an important open research problem for more than 50 years 9 . Despite recent progress 10 – 14 , existing methods fall far short of atomic accuracy, especially when no homologous structure is available. Here we provide the first computational method that can regularly predict protein structures with atomic accuracy even in cases in which no similar structure is known. We validated an entirely redesigned version of our neural network-based model, AlphaFold, in the challenging 14th Critical Assessment of protein Structure Prediction (CASP14) 15 , demonstrating accuracy competitive with experimental structures in a majority of cases and greatly outperforming other methods. Underpinning the latest version of AlphaFold is a novel machine learning approach that incorporates physical and biological knowledge about protein structure, leveraging multi-sequence alignments, into the design of the deep learning algorithm. AlphaFold predicts protein structures with an accuracy competitive with experimental structures in the majority of cases using a novel deep learning architecture.
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            Gapped BLAST and PSI-BLAST: a new generation of protein database search programs.

            S Altschul (1997)
            The BLAST programs are widely used tools for searching protein and DNA databases for sequence similarities. For protein comparisons, a variety of definitional, algorithmic and statistical refinements described here permits the execution time of the BLAST programs to be decreased substantially while enhancing their sensitivity to weak similarities. A new criterion for triggering the extension of word hits, combined with a new heuristic for generating gapped alignments, yields a gapped BLAST program that runs at approximately three times the speed of the original. In addition, a method is introduced for automatically combining statistically significant alignments produced by BLAST into a position-specific score matrix, and searching the database using this matrix. The resulting Position-Specific Iterated BLAST (PSI-BLAST) program runs at approximately the same speed per iteration as gapped BLAST, but in many cases is much more sensitive to weak but biologically relevant sequence similarities. PSI-BLAST is used to uncover several new and interesting members of the BRCT superfamily.
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              Jalview Version 2—a multiple sequence alignment editor and analysis workbench

              Summary: Jalview Version 2 is a system for interactive WYSIWYG editing, analysis and annotation of multiple sequence alignments. Core features include keyboard and mouse-based editing, multiple views and alignment overviews, and linked structure display with Jmol. Jalview 2 is available in two forms: a lightweight Java applet for use in web applications, and a powerful desktop application that employs web services for sequence alignment, secondary structure prediction and the retrieval of alignments, sequences, annotation and structures from public databases and any DAS 1.53 compliant sequence or annotation server. Availability: The Jalview 2 Desktop application and JalviewLite applet are made freely available under the GPL, and can be downloaded from www.jalview.org Contact: g.j.barton@dundee.ac.uk
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                Author and article information

                Contributors
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: InvestigationRole: ValidationRole: VisualizationRole: Writing – original draftRole: Writing – review & editing
                Role: Investigation
                Role: Investigation
                Role: Investigation
                Role: InvestigationRole: Visualization
                Role: Investigation
                Role: Formal analysisRole: InvestigationRole: Visualization
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: Funding acquisitionRole: InvestigationRole: Project administrationRole: SupervisionRole: ValidationRole: VisualizationRole: Writing – original draftRole: Writing – review & editing
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: Funding acquisitionRole: InvestigationRole: Project administrationRole: SupervisionRole: ValidationRole: VisualizationRole: Writing – original draftRole: Writing – review & editing
                Role: Editor
                Journal
                PLoS Genet
                PLoS Genet
                plos
                PLOS Genetics
                Public Library of Science (San Francisco, CA USA )
                1553-7390
                1553-7404
                8 December 2022
                December 2022
                : 18
                : 12
                : e1010547
                Affiliations
                [1 ] Department of Molecular Life Science (DMLS), University of Zurich, Zurich, Switzerland
                [2 ] Friedrich Miescher Laboratory of the Max Planck Society, Tübingen, Germany
                [3 ] Research Institute of Molecular Pathology (IMP), Vienna BioCenter, Vienna, Austria
                Stowers Institute for Medical Research, UNITED STATES
                Author notes

                The authors have declared that no competing interests exist.

                Author information
                https://orcid.org/0000-0001-6251-2747
                https://orcid.org/0000-0002-6904-0284
                https://orcid.org/0000-0003-0185-6049
                Article
                PGENETICS-D-22-01170
                10.1371/journal.pgen.1010547
                9767379
                36480577
                c451eb9a-2dfe-4811-853a-77281f13a748
                © 2022 Kabakci et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 12 October 2022
                : 28 November 2022
                Page count
                Figures: 7, Tables: 0, Pages: 41
                Funding
                Funded by: funder-id http://dx.doi.org/10.13039/501100001711, Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung;
                Award ID: 31003A_179433
                Award Recipient :
                Funded by: Max-Planck Society
                Award Recipient :
                Funded by: Deutsche Forschungsgemeinschaft (DFG)
                Award ID: WE 6513/2-1
                Award Recipient :
                The research was supported by funds obtained from the Swiss National Science Foundation ( www.snf.ch), grant number 31003A_179433 (CFL), from the Max-Planck Society (JRW) and from the German Research Foundation ( www.dfg.de), grant number WE 6513/2-1 (JRW). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Biology and Life Sciences
                Cell Biology
                Cellular Types
                Animal Cells
                Germ Cells
                Sperm
                Spermatocytes
                Biology and life sciences
                Biochemistry
                Proteins
                DNA-binding proteins
                Research and Analysis Methods
                Precipitation Techniques
                Immunoprecipitation
                Co-Immunoprecipitation
                Research and Analysis Methods
                Animal Studies
                Experimental Organism Systems
                Model Organisms
                Drosophila Melanogaster
                Research and Analysis Methods
                Model Organisms
                Drosophila Melanogaster
                Research and Analysis Methods
                Animal Studies
                Experimental Organism Systems
                Animal Models
                Drosophila Melanogaster
                Biology and Life Sciences
                Zoology
                Entomology
                Insects
                Drosophila
                Drosophila Melanogaster
                Biology and Life Sciences
                Organisms
                Eukaryota
                Animals
                Invertebrates
                Arthropoda
                Insects
                Drosophila
                Drosophila Melanogaster
                Biology and Life Sciences
                Zoology
                Animals
                Invertebrates
                Arthropoda
                Insects
                Drosophila
                Drosophila Melanogaster
                Biology and Life Sciences
                Cell Biology
                Cell Processes
                Cell Cycle and Cell Division
                Meiosis
                Biology and Life Sciences
                Cell Biology
                Chromosome Biology
                Meiosis
                Biology and Life Sciences
                Cell Biology
                Chromosome Biology
                Chromosomes
                Homologous Chromosomes
                Physical Sciences
                Chemistry
                Polymer Chemistry
                Monomers
                Glycerol
                Biology and Life Sciences
                Cell Biology
                Cell Processes
                Cell Cycle and Cell Division
                Anaphase
                Custom metadata
                vor-update-to-uncorrected-proof
                2022-12-20
                All relevant data are within the manuscript and its Supporting information files.

                Genetics
                Genetics

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