Heterodimeric complexes of Hop2 and Mnd1 function with Dmc1 to promote meiotic homolog juxtaposition and strand assimilation

Chen, Yikai; Leng, Chih‐Hsiang; Olivares, Heidi; Lee, Ming‐Hui; Chang, Yuan-Chih; Kung, Wen-Mei; Ti, Shih-Chieh; Lo, Yu-Hui; Wang, Andrew H.-J.; Chang, Chia-Seng; Bishop, Douglas K.; Hsueh, Yi‐Ping; Wang, Ting-Fang

doi:10.1073/pnas.0404195101

Cited by 110 publications

(179 citation statements)

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“…These accessory factors stimulate the assembly of the Dmc1 presynaptic filament or the homologous DNA pairing activity of the presynaptic filament (20,23,25), whereas Rdh54 also appears to catalyze the removal of Dmc1 from double-stranded DNA (28). We have recently identified RAD51AP1 as a novel vertebrate accessory factor of DMC1 by showing that it stimulates the DMC1-mediated D-loop reaction.…”

Section: Homologous Recombination (Hr)mentioning

confidence: 99%

“…Several accessory proteins of budding yeast Dmc1 have been identified, including Mei5-Sae3 (Sfr1-Swi5 in the fission yeast) (20 -22), Hop2-Mnd1 (13,(23)(24)(25) and Rdh54 (12,26,27). These accessory factors stimulate the assembly of the Dmc1 presynaptic filament or the homologous DNA pairing activity of the presynaptic filament (20,23,25), whereas Rdh54 also appears to catalyze the removal of Dmc1 from double-stranded DNA (28).…”

Section: Homologous Recombination (Hr)mentioning

confidence: 99%

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RAD51-associated Protein 1 (RAD51AP1) Interacts with the Meiotic Recombinase DMC1 through a Conserved Motif

Dunlop

Dray

Zhao

et al. 2011

Journal of Biological Chemistry

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Background: RAD51AP1 physically and functionally interacts with the RAD51 and DMC1 recombinases. Results: Mutational analysis showed that the WVPP sequence in RAD51AP1 is part of the DMC1-specific interaction motif. Conclusion: RAD51AP1 interacts with RAD51 and DMC1 through distinct motifs. Significance: RAD51AP1 likely functions in meiotic homologous recombination by enhancing the recombinase activity of both RAD51 and DMC1.

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Section: Homologous Recombination (Hr)mentioning

confidence: 99%

Section: Homologous Recombination (Hr)mentioning

confidence: 99%

RAD51-associated Protein 1 (RAD51AP1) Interacts with the Meiotic Recombinase DMC1 through a Conserved Motif

Dunlop

Dray

Zhao

et al. 2011

Journal of Biological Chemistry

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“…), although Rad54 may normally partner with Rad51 and Tid1/Rdh54 with Dmc1. Finally, in vivo experiments suggest another accessory protein, Hop2-Mnd1, stimulates Dmc1-dependent and not Rad51-dependent recombination in vivo (Tsubouchi and Roeder 2003;Chen et al 2004;Henry et al 2006). Although these accessory factor differences may allow for distinct regulation of the two recombinases, we reiterate that the ability of each of the recombinases to promote substantial strand invasion in the absence of the other indicates a significant degree of functional redundancy in vivo (Schwacha and Kleckner 1997;Shinohara et al 1997;Zenvirth et al 1997;Bishop et al 1999;Tsubouchi and Roeder 2003).…”

mentioning

confidence: 99%

Red-Hed regulation: recombinase Rad51, though capable of playing the leading role, may be relegated to supporting Dmc1 in budding yeast meiosis: Figure 1.

Sheridan

Bishop²

2006

Genes Dev.

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DNA strand exchange is the central process of homologous recombination. In budding yeast, this reaction is catalyzed by the recombinases Rad51 and Dmc1. Rad51 is responsible for recombinational repair of DNA damage during mitosis and is also important during meiotic recombination. Dmc1 is only expressed during meiosis and is required for meiotic recombination. The discovery that these two different recombinases are needed for normal levels of meiotic recombination in budding yeast raised the question of how the functions of these proteins relate to one another. The paper by Tsubouchi and Roeder (2006) in this issue of Genes & Development represents important progress toward what is apparently a rather complex answer. Tsubouchi and Roeder (2006) report discovery of a novel meiosis-specific protein, Hed1, which appears to inhibit Rad51 when Dmc1 is absent. The authors show mutation of the HED1 gene allows cells to bypass the meiotic arrest caused by a dmc1 mutation and resolve meiosis-specific double-strand breaks (DSBs) using Rad51. A hed1 mutation can also suppress the defects caused by mutation of HOP2, which codes for a Dmc1 accessory factor. Two-hybrid experiments show that Hed1 and Rad51 can interact directly and immuno-staining shows that subnuclear foci formed by Hed1 and Rad51 colocalize. Together these results imply that Hed1's influence on Rad51 activity is direct. Furthermore, expression of Hed1 in mitotic cells provided evidence that Hed1 expression can be sufficient to inhibit Rad51-dependent repair of mitotic DNA damage.A reasonable interpretation of these results is that the meiotic recombination machinery of budding yeast is regulated such that Dmc1 carries out most strand exchange. Tsubouchi and Roeder's (2006) results also add to evidence indicating that Rad51 is capable of replacing Dmc1's function under certain circumstances. Here, we place these new findings in the context of previous observations and present a model to explain how Rad51 and Dmc1 may cooperate to promote interhomolog recombination in budding yeast, while at the same time accounting for the observed functional redundancy. We further speculate as to how the functional relationship of Rad51 and Dmc1 may have evolved.The notion that Rad51 activity is blocked during meiosis is not new. Previous work showed that Dmc1-independent recombination is inhibited by proteins associated with axial elements (Schwacha and Kleckner 1997;Xu et al. 1997;Bishop et al. 1999;Niu et al. 2005) proteinaceous structures that organize pairs of sister chromatids into two parallel sets of loops by binding at their base. The assembly of the synaptonemal complex brings an axial element with its pair of sisters into close parallel alignment with another axial element holding the homologous sister pair. Three interacting axis-associated proteins-Red1, Hop1, and Mek1-regulate recombination by suppressing Dmc1-independent recombination and, in the case of Red1 and Hop1, by enhancing the efficiency of DSB formation in a locus-specific manner (Rockmill and Roeder...

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“…Factors such as Rad52, Rad54, and BRCA2 mediate the homologous pairing and strand exchange reaction promoted by Rad51 (17)(18)(19). On the other hand, the mouse TBPIP/Hop2 protein (16) and the yeast Hop2-Mnd1 complex (20) stimulate the Dmc1-dependent homologous pairing. Furthermore, a Dmc1-specific mediator, the Sae3-Mei5 complex, has been found in Saccharomyces cerevisiae and may promote the assembly of Dmc1 on the doublestranded break site (21,22), although the Schizosaccharomyces pombe Swi5-Sfr1 complex, composed of homologues of the S. cerevisiae Sae3-Mei5 complex, functions with Rad51 (23).…”

mentioning

confidence: 99%

Role of the N-terminal Domain of the Human DMC1 Protein in Octamer Formation and DNA Binding

Kinebuchi¹,

Kagawa²,

Kurumizaka

et al. 2005

Journal of Biological Chemistry

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The DMC1 protein, a eukaryotic homologue of RecA that shares significant amino acid identity with RAD51, exhibits two oligomeric DNA binding forms, an octameric ring and a helical filament. In the crystal structure of the octameric ring form, the DMC1 N-terminal domain (1-81 amino acid residues) was highly flexible, with multiple conformations. On the other hand, the N-terminal domain of Rad51 makes specific interactions with the neighboring ATPase domain in the helical filament structure. To gain insights into the functional role of the N-terminal domain of DMC1, we prepared a deletion mutant, DMC1-(82-340), that lacks the N-terminal 81 amino acid residues from the human DMC1 protein.Analytical ultracentrifugation experiments revealed that, whereas full-length DMC1 forms a octamer, DMC1-(82-340) is a heptamer. Furthermore, DNA binding experiments showed that DMC1-(82-340) was completely defective in both single-stranded and double-stranded DNA binding activities. Therefore, the N-terminal domain of DMC1 is required for the formation of the octamer, which may support the proper DNA binding activity of the DMC1 protein.Recombination is the exchange or transfer of information between DNA molecules, and it occurs in all organisms. During meiosis, homologous recombination takes place as part of the normal meiotic process in order to generate genetic diversity. Through homologous recombination in meiosis, the genes from each parent recombine at frequencies 100-to 1000-fold higher than those of vegetative cells, leading to different genomic signatures (1, 2). In meiotic homologous recombination, doublestranded breaks are introduced by the Spo11 protein, and 3Ј-single-stranded tails are produced at the double-stranded break sites (3)(4)(5). Then, the homologous pairing proteins, such as Rad51 and Dmc1, and their activators are recruited to the single-stranded tails. The Rad51 and Dmc1 proteins are eukaryotic homologues of the bacterial RecA protein that promotes homologous pairing between single-stranded DNA (ssDNA) 1 and double-stranded DNA (dsDNA). Dmc1 is a meiosis-specific factor, whereas Rad51 is required for both meiotic and mitotic homologous recombination (6, 7).DMC1 and RAD51 share ϳ54% amino acid sequence identity (8). Like RecA, Rad51 and Dmc1 promote homologous pairing between two DNA molecules in vitro (9 -16). Despite these similarities, Rad51 and Dmc1 require different factors to promote homologous pairing efficiently. Factors such as Rad52, Rad54, and BRCA2 mediate the homologous pairing and strand exchange reaction promoted by . On the other hand, the mouse TBPIP/Hop2 protein (16) and the yeast Hop2-Mnd1 complex (20) stimulate the Dmc1-dependent homologous pairing. Furthermore, a Dmc1-specific mediator, the Sae3-Mei5 complex, has been found in Saccharomyces cerevisiae and may promote the assembly of Dmc1 on the doublestranded break site (21,22), although the Schizosaccharomyces pombe Swi5-Sfr1 complex, composed of homologues of the S. cerevisiae Sae3-Mei5 complex, functions with Rad51 (23).The S. cerev...

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Heterodimeric complexes of Hop2 and Mnd1 function with Dmc1 to promote meiotic homolog juxtaposition and strand assimilation

Cited by 110 publications

References 44 publications

RAD51-associated Protein 1 (RAD51AP1) Interacts with the Meiotic Recombinase DMC1 through a Conserved Motif

RAD51-associated Protein 1 (RAD51AP1) Interacts with the Meiotic Recombinase DMC1 through a Conserved Motif

Red-Hed regulation: recombinase Rad51, though capable of playing the leading role, may be relegated to supporting Dmc1 in budding yeast meiosis: Figure 1.

Role of the N-terminal Domain of the Human DMC1 Protein in Octamer Formation and DNA Binding

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