Structure and DNA bridging activity of the essential Rec114–Mei4 trimer interface

Liu, Kaixian; Pu, Stephen; Eliezer, David; Liu, Shixin; Keeney, Scott

doi:10.1101/2023.01.18.524603

Cited by 6 publications

(6 citation statements)

References 66 publications

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“…In this model, the open and compact conformations of TOPOVIBL allowing interaction or not with REC114, might represent an active and inactive state for TOPOVIL, respectively. Accumulation of proteins that create a matrix and a condensate-like environment to favor protein-protein interactions also might favor SPO11 dimerization, as proposed in alternative studies (24, 26, 27)(27). As observed in archaea, the SPO11 dimerization could then induce conformational changes of this catalytic subunit, making it efficient for DSB formation activity (Step 3, Fig.…”

Section: Discussionmentioning

confidence: 89%

“…The DNA topological environment sensed by TOPOVIBL could be one of these parameters. The MEI4/REC114 (1:2) complex also might act as a clamp to hold together the two SPO11 subunits (24–26) (28). This clamping activity could be mediated by the C-terminal helix of TOPOVIBL that interacts with REC114 and possibly by TOPOVIBL dynamic conformation revealed by our SAXS data (Step 2, Fig.5).…”

Section: Discussionmentioning

confidence: 99%

“…Recently, it was proposed that the yeast Rec114, Mei4 and Mer2 DSB accessory factors assemble in a complex. This complex forms condensate-like structures in the presence of DNA that directly interacts with Rec102/Rec104 and thus might favor the core complex dimerization (23)(24)(25)(26) (27).…”

Section: Introductionmentioning

confidence: 99%

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TOPOVIBL function in meiotic DSB formation: new insights from its biochemical and structural characterization

Diagouraga,

Tambones,

Carivenc

et al. 2023

Preprint

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The TOPOVIL complex catalyzes the formation of DNA double strand breaks (DSB) that initiate meiotic homologous recombination, an essential step for chromosome segregation and genetic diversity during gamete production. TOPOVIL is composed of two subunits (SPO11 and TOPOVIBL) and is evolutionarily related to the archaeal TopoVI topoisomerase complex. SPO11 is the TopoVIA subunit orthologue and carries the DSB formation catalytic activity. TOPOVIBL shares homology with the TopoVIB ATPase subunit. TOPOVIBL is essential for meiotic DSB formation, but its molecular function remains elusive, partly due to the lack of biochemical studies. Here, we purified TOPOVIBLΔC25 and characterized its structure and mode of actionin vitro. Our structural analysis revealed that TOPOVIBLΔC25 adopts a dynamic conformation in solution and our biochemical study showed that the protein remains monomeric upon incubation with ATP, which correlates with the absence of ATP binding. Moreover, TOPOVIBLΔC25 interacted with DNA, with a preference for some geometries, suggesting that TOPOVIBL senses specific DNA architectures. Altogether, our study identified specific TOPOVIBL features that might help to explain how TOPOVIL function evolved toward a DSB formation activity in meiosis.

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Section: Discussionmentioning

confidence: 89%

Section: Discussionmentioning

confidence: 99%

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TOPOVIBL function in meiotic DSB formation: new insights from its biochemical and structural characterization

Diagouraga,

Tambones,

Carivenc

et al. 2023

Preprint

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“…In Saccharomyces cerevisiae, heterotrimeric Rec114-Mei4 complexes or homotetramers of Mer2 (homologous to IHO1 in mice) bind DNA in a highly cooperative manner in vitro, forming large nucleoprotein condensates containing many protein copies (Claeys Bouuaert et al, 2021). A minimal trimerization domain from both yeast Rec114-Mei4 and mouse REC114-MEI4 is sufficient for condensate formation (Liu et al, 2023), suggesting a possible connection between the condensates characterized for the yeast proteins and the formation of small foci and blobs in vivo in mice. Although a detailed understanding of the mechanism of mo-2-associated blob formation remains elusive, we consider it likely that the multivalent ANKRD31 scaffold works interdependently with its binding partners to assemble condensates on mo-2 chromatin.…”

Section: Discussionmentioning

confidence: 99%

Essential roles of the ANKRD31-REC114 interaction in meiotic recombination and mouse spermatogenesis

Kim

et al. 2023

Preprint

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DNA double-strand breaks (DSBs) initiate meiotic recombina-tion. ANKRD31 recently emerged as a DSB regulator particularly important in the pseudoautosomal regions (PARs) of sex chromosomes. ANKRD31 interacts with multiple proteins, including DSB-promoting REC114. To test if this interaction is important, we generated mice with Ankrd31 mutations that either reduced (missense) or eliminated (C-terminal truncation) the ANKRD31-REC114 interaction without diminishing contacts with other partners. Eliminating the interaction mimicked an Ankrd31 null, with delayed DSB formation, defective DSB repair, and altered DSB locations including absence of PAR breaks. When the ANKRD31-REC114 interaction was instead attenuated, DSB formation was again delayed globally, but DSB locations and repair were affected little if at all. The missense Ankrd31 allele showed a dosage effect, wherein combining it with the null or C-terminal truncation allele resulted in intermediate phenotypes. Our results show that ANKRD31 function is critically dependent on its interaction with REC114, and that defects in ANKRD31 activity correlate with severity of interaction disruption.

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“…Mer2 also efficiently binds nucleosomes in vitro 29,73 . DNA binding of DSB factors also shows considerable conservation 73,74 . Thus, the in vitro clusters of DNA-bound DSB-factors of budding yeast likely model in vivo DSB-factor clusters which enable DSB activity in diverse taxa including mammals.…”

Section: Enabling Seeding and Growth Of Dsb-factor Clusters On Chromo...mentioning

confidence: 99%

Seeding the meiotic DNA break machinery and initiating recombination on chromosome axes

Dereli,

Telychko,

Papanikos

et al. 2024

Nat Commun

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Programmed DNA double-strand break (DSB) formation is a crucial feature of meiosis in most organisms. DSBs initiate recombination-mediated linking of homologous chromosomes, which enables correct chromosome segregation in meiosis. DSBs are generated on chromosome axes by heterooligomeric focal clusters of DSB-factors. Whereas DNA-driven protein condensation is thought to assemble the DSB-machinery, its targeting to chromosome axes is poorly understood. We uncover in mice that efficient biogenesis of DSB-machinery clusters requires seeding by axial IHO1 platforms. Both IHO1 phosphorylation and formation of axial IHO1 platforms are diminished by chemical inhibition of DBF4-dependent kinase (DDK), suggesting that DDK contributes to the control of the axial DSB-machinery. Furthermore, we show that axial IHO1 platforms are based on an interaction between IHO1 and the chromosomal axis component HORMAD1. IHO1-HORMAD1-mediated seeding of the DSB-machinery on axes ensures sufficiency of DSBs for efficient pairing of homologous chromosomes. Without IHO1-HORMAD1 interaction, residual DSBs depend on ANKRD31, which enhances both the seeding and the growth of DSB-machinery clusters. Thus, recombination initiation is ensured by complementary pathways that differentially support seeding and growth of DSB-machinery clusters, thereby synergistically enabling DSB-machinery condensation on chromosomal axes.

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Structure and DNA bridging activity of the essential Rec114–Mei4 trimer interface

Cited by 6 publications

References 66 publications

TOPOVIBL function in meiotic DSB formation: new insights from its biochemical and structural characterization

TOPOVIBL function in meiotic DSB formation: new insights from its biochemical and structural characterization

Essential roles of the ANKRD31-REC114 interaction in meiotic recombination and mouse spermatogenesis

Seeding the meiotic DNA break machinery and initiating recombination on chromosome axes

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