Two structurally mobile regions control the conformation and function of metamorphic meiotic HORMAD proteins
Consuelo BarrosoJosh P. PrincePunam RattuDaimona KundéNuria FerrándizSyma KhalidEnrique Martínez-Pérez
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Abstract:
Abstract Metamorphic HORMA domain proteins (HORMADs) nucleate protein complex formation by refolding their mobile safety belt region to bind short motifs on interactors. Meiotic HORMADs (mHORMADs) bind proteinaceous axial elements to orchestrate complex chromosomal events that underpin fertility, including pairing and recombination between homologous chromosomes. However, the mechanisms supporting the diverse roles of mHORMADs remain unclear. Here, we show that mHORMADs have a second structurally mobile region, the β5-αC loop, which controls mHORMAD conformation and function. Molecular dynamics and in vivo approaches show that functional specialisation of C. elegans paralogs HTP-1 and HTP-2 depends on the interplay between their β5-αC loop and safety belt. The β5-αC loop can interact with the same HORMA core surface as the safety belt, forming a “loop engaged” conformation. The β5-αC loop HORMA core interaction is essential for axis loading of HTP-1 and its paralog HTP-3, and is also present in yeast, plant, and mammalian mHORMADs, suggesting that it represents a conserved functional feature of mHORMADs. Our study reveals that mHORMADs have expanded the bimodal folding landscape first identified in Mad2, paving the way to elucidate how non-canonical HORMAD conformations control meiotic chromosome function to ensure fertility.Keywords:
Folding (DSP implementation)
During meiosis, one round of genome duplication is followed by two rounds of chromosome segregation, resulting in the halving of the genetic complement and the formation of haploid reproductive cells. In most organisms, intimate juxtaposition of homologous chromosomes and homologous recombination during meiotic prophase are required for meiotic success. Here we present a general protocol for visualizing chromosomal proteins and homolog interaction on surface-spread nuclei and a widely used protocol for analyzing meiotic recombination based on an engineered hotspot referred to as HIS4::LEU2.
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During the first meiotic division, the segregation of homologous chromosomes depends on the physical association of the recombined homologous DNA molecules. The physical tension due to the sites of crossing-overs (COs) is essential for the meiotic spindle to segregate the connected homologous chromosomes to the opposite poles of the cell. This equilibrated partition of homologous chromosomes allows the first meiotic reductional division. Thus, the segregation of homologous chromosomes is dependent on their recombination. In this review, we will detail the recent advances in the knowledge of the mechanisms of recombination and bivalent formation in plants. In plants, the absence of meiotic checkpoints allows observation of subsequent meiotic events in absence of meiotic recombination or defective meiotic chromosomal axis formation such as univalent formation instead of bivalents. Recent discoveries, mainly made in Arabidopsis, rice, and maize, have highlighted the link between the machinery of double-strand break (DSB) formation and elements of the chromosomal axis. We will also discuss the implications of what we know about the mechanisms regulating the number and spacing of COs (obligate CO, CO homeostasis, and interference) in model and crop plants.
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Chromosomal crossover
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Chromosome pairing
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Sexual reproduction prevails among eukaryotic organisms. The problem of advantage of sexual reproduction over asexual reproduction remains a subject of not stopping discussions. According to one of the hypotheses, sexual reproduction and homologous recombination which accompanies gamete formation during meiosis has arisen to increase genetic variability and, as consequence, a fitness of organisms. Many researches show that homologous recombination play an important role in reparation of DNA in various groups of organisms irrespective of the way of their reproduction. Involvement of recombination in meiosis, however, is impossible to explain only by DNA repair functions. The hypothesis, that a recombination in the course of sexual process is a source of variability, also is not capable to explain existence of this process well. There is convincing evidence that the homologous recombination in meiosis is necessary for formation of bivalents. A physical connection between homologous chromosomes that is formed by recombination is required for correct chromosome segregation during meiotic division and formation of gametes of full value.
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Ectopic recombination
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Chromosomal crossover
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Until recently, most of our understanding of meiotic recombination has come from studies of lower eukaryotes. However, over the past few years several components of the mammalian meiotic recombination pathway have been identified, and new molecular and cytological approaches to the analysis of mammalian meiosis have been developed. In this review, we discuss recent advances in three areas: the application of new techniques to study genome-wide levels of recombination in individual meioses; studies analyzing temporal aspects of the mammalian recombination pathway; and studies linking the genesis of human trisomies to alterations in meiotic exchange patterns.
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Meiotic recombination is a highly complex process resulting in the formation of reciprocal genetic exchanges (crossovers) between homologous chromosomes during meiotic prophase I. Crossovers generate genetic diversity and are required for the accurate segregation of homologous chromosomes in most organisms. Therefore, alterations in meiotic recombination contribute to gamete aneuploidy. The molecular mechanisms that play during meiotic recombination have been extensively studied in fungi, and especially in the budding yeast Saccharomyces cerevisiae. However, recent studies focusing on mammalian meiosis have given new informations on how meiotic crossovers form and how their distribution and number are regulated. In this chapter, we give an overview of the current knowledge of meiotic recombination in mammals.
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Chromosomal crossover
FLP-FRT recombination
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