Live imaging and biophysical modeling support a button-based mechanism of somatic homolog pairing in Drosophila

Child, Myron; Bateman, Jack R.; Jahangiri, Amir; Reimer, Armando; Lammers, Nicholas C; Sabouni, Nica; Villamarin, Diego; McKenzie‐Smith, Grace C.; Johnson, Justine E.; Jost, Daniel; García, Hernán G.

doi:10.7554/elife.64412

Cited by 24 publications

(21 citation statements)

References 80 publications

(130 reference statements)

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“…FISH analyses with embryos have indicated that the pairing of homologous chromosomes is largely abolished during progression through mitosis, followed by rapid restoration within the first 20 minutes of interphase [ 16 ]. Overall the most recent studies [ 17 – 19 ] support a model for homolog pairing based on “buttons”, i.e. high affinity regions interspersed along the chromosomes where pairing is initiated followed perhaps by zipper-like spreading.…”

Section: Introductionmentioning

confidence: 99%

Bivalent individualization during chromosome territory formation in Drosophila spermatocytes by controlled condensin II protein activity and additional force generators

Vernizzi

Lehner

2021

PLoS Genet

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Reduction of genome ploidy from diploid to haploid necessitates stable pairing of homologous chromosomes into bivalents before the start of the first meiotic division. Importantly, this chromosome pairing must avoid interlocking of non-homologous chromosomes. In spermatocytes of Drosophila melanogaster, where homolog pairing does not involve synaptonemal complex formation and crossovers, associations between non-homologous chromosomes are broken up by chromosome territory formation in early spermatocytes. Extensive non-homologous associations arise from the coalescence of the large blocks of pericentromeric heterochromatin into a chromocenter and from centromere clustering. Nevertheless, during territory formation, bivalents are moved apart into spatially separate subnuclear regions. The condensin II subunits, Cap-D3 and Cap-H2, have been implicated, but the remarkable separation of bivalents during interphase might require more than just condensin II. For further characterization of this process, we have applied time-lapse imaging using fluorescent markers of centromeres, telomeres and DNA satellites in pericentromeric heterochromatin. We describe the dynamics of the disruption of centromere clusters and the chromocenter in normal spermatocytes. Mutations in Cap-D3 and Cap-H2 abolish chromocenter disruption, resulting in excessive chromosome missegregation during M I. Chromocenter persistence in the mutants is not mediated by the special system, which conjoins homologs in compensation for the absence of crossovers in Drosophila spermatocytes. However, overexpression of Cap-H2 precluded conjunction between autosomal homologs, resulting in random segregation of univalents. Interestingly, Cap-D3 and Cap-H2 mutant spermatocytes displayed conspicuous stretching of the chromocenter, as well as occasional chromocenter disruption, suggesting that territory formation might involve forces unrelated to condensin II. While the molecular basis of these forces remains to be clarified, they are not destroyed by inhibitors of F actin and microtubules. Our results indicate that condensin II activity promotes chromosome territory formation in co-operation with additional force generators and that careful co-ordination with alternative homolog conjunction is crucial.

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Section: Introductionmentioning

confidence: 99%

Bivalent individualization during chromosome territory formation in Drosophila spermatocytes by controlled condensin II protein activity and additional force generators

Vernizzi

Lehner

2021

PLoS Genet

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“…Mod(mdg4)_T (also designated as 67.2 or 2.2), the most extensively characterized isoform expressed from the complex mod(mdg4) locus, interacts and co-operates with several chromatin architectural proteins (including CP190, HIPP1 and SuHw) at the gypsy insulator [ 37 ]. Moreover, Mod(mdg4)_T in combinations with chromatin architectural proteins in various combinations is generally enriched at boundaries between topologically associated chromatin domains and also at button loci that promote the somatic pairing of homologous chromosomes [ 55 , 56 ]. Recently, Mod(mdg4) function has been implicated in a striking example of chromosome pairing-dependent regulation of physiological gene expression [ 57 ].…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2022

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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.

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“…Several previous computational models have been described to represent meiotic homolog pairing [2][3][4][5][6][7]. These models have, in general, ignored the possibility of entanglement, by assuming that chromosomes are able to pass through one another.…”

Section: Plos Computational Biologymentioning

confidence: 99%

Modeling cell biological features of meiotic chromosome pairing to study interlock resolution

2022

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During meiosis, homologous chromosomes become associated side by side in a process known as homologous chromosome pairing. Pairing requires long range chromosome motion through a nucleus that is full of other chromosomes. It remains unclear how the cell manages to align each pair of chromosomes quickly while mitigating and resolving interlocks. Here, we use a coarse-grained molecular dynamics model to investigate how specific features of meiosis, including motor-driven telomere motion, nuclear envelope interactions, and increased nuclear size, affect the rate of pairing and the mitigation/resolution of interlocks. By creating in silico versions of three yeast strains and comparing the results of our model to experimental data, we find that a more distributed placement of pairing sites along the chromosome is necessary to replicate experimental findings. Active motion of the telomeric ends speeds up pairing only if binding sites are spread along the chromosome length. Adding a meiotic bouquet significantly speeds up pairing but does not significantly change the number of interlocks. An increase in nuclear size slows down pairing while greatly reducing the number of interlocks. Interestingly, active forces increase the number of interlocks, which raises the question: How do these interlocks resolve? Our model gives us detailed movies of interlock resolution events which we then analyze to build a step-by-step recipe for interlock resolution. In our model, interlocks must first translocate to the ends, where they are held in a quasi-stable state by a large number of paired sites on one side. To completely resolve an interlock, the telomeres of the involved chromosomes must come in close proximity so that the cooperativity of pairing coupled with random motion causes the telomeres to unwind. Together our results indicate that computational modeling of homolog pairing provides insight into the specific cell biological changes that occur during meiosis.

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Live imaging and biophysical modeling support a button-based mechanism of somatic homolog pairing in Drosophila

Cited by 24 publications

References 80 publications

Bivalent individualization during chromosome territory formation in Drosophila spermatocytes by controlled condensin II protein activity and additional force generators

Bivalent individualization during chromosome territory formation in Drosophila spermatocytes by controlled condensin II protein activity and additional force generators

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

Modeling cell biological features of meiotic chromosome pairing to study interlock resolution

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