Structure of a filament of stacked octamers of human DMC1 recombinase

Du, Liqin; Luo, Yu

doi:10.1107/s1744309113005678

Cited by 7 publications

(9 citation statements)

References 49 publications

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“…SWISS-MODEL (Arnold et al , 2006) indicated that the HvDMC1 3D protein formed an L-shape structure (Fig. 4B), as previously predicted (Kinebuchi et al , 2004; Du and Luo, 2013). Similarly, the DMC1 des5 protein model also predicts an L-shape structure but has a slightly different 3D conformation when superposed onto the wild-type protein (Fig.…”

Section: Resultssupporting

confidence: 78%

“…4C). The modelling indicated that the majority of the DMC1 protein in des5 is unchanged except for the region between the 200th and 350th amino acid (Fig.4D), which could affect protein stability and/or polymerization of the nucleofilament (Du and Luo, 2013).…”

Section: Resultsmentioning

confidence: 99%

“…DMC1 was initially described in yeast (Bishop et al , 1992) as a homolog of the bacterial strand exchange protein RECA and is highly conserved amongst eukaryotes, including plants (Bishop et al , 1992; Habu et al , 1996; Klimyuk and Jones, 1997; Doutriaux et al , 1998; Passy et al , 1999; Kathiresan et al , 2002; Devisetty et al , 2010). The recombinases DMC1 and RAD51 capture, for repair, the 3′ overhangs generated by resected double-strand breaks catalysed by SPO11, with RAD51 supporting invasion of a homologous DNA template by DMC1 (Sheridan et al , 2008; Da Ines et al , 2013; Du and Luo, 2013; Lorenz et al , 2014; Lichten et al , 2015; MacQueen, 2015). In mammals, dmc1 mutants are deficient for synapsis and homologous pairing and lead to severe sterility due to prophase arrest (Pittman et al , 1998; Yoshida et al , 1998).…”

Section: Introductionmentioning

confidence: 99%

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desynaptic5 carries a spontaneous semi-dominant mutation affecting Disrupted Meiotic cDNA 1 in barley

Colas

Barakate

Macaulay

et al. 2019

Journal of Experimental Botany

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Despite conservation of the process of meiosis, recombination landscapes vary between species, with large genome grasses such as barley ( Hordeum vulgare L.) exhibiting a pattern of recombination that is very heavily skewed to the ends of chromosomes. We have been using a collection of semi-sterile desynaptic meiotic mutant lines to help elucidate how recombination is controlled in barley and the role of the corresponding wild-type (WT) meiotic genes within this process. Here we applied a combination of genetic segregation analysis, cytogenetics, and immunocytology to genetically map and characterize the meiotic mutant desynaptic5 ( des5 ). We identified an exonic insertion in the positional candidate ortholog of Disrupted Meiotic cDNA 1 ( HvDMC1 ) on chromosome 5H of des5 . des5 exhibits a severe meiotic phenotype with disturbed synapsis, reduced crossovers, and chromosome mis-segregation. The meiotic phenotype and reduced fertility of des5 is similarly observed in Hvdmc1 RNAi transgenic plants and HvDMC1 p:GusPlus reporter lines show DMC1 expression specifically in the developing inflorescence. The des5 mutation maintains the reading frame of the gene and exhibits semi-dominance with respect to recombination in the heterozygote indicating the value of non-knockout mutations for dissection of the control of recombination in the early stages of meiosis.

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Section: Resultssupporting

confidence: 78%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

desynaptic5 carries a spontaneous semi-dominant mutation affecting Disrupted Meiotic cDNA 1 in barley

Colas

Barakate

Macaulay

et al. 2019

Journal of Experimental Botany

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“…DMC1 : is a meiosis-specific recombinase interacting with several DNA repair proteins in the FA pathway [ 140 ], thus it is essential for meiotic homologous recombination and DBS repair [ 141 , 142 , 143 ]. The lack of this protein results in a block at the leptotene or zygotene stage of meiotic prophase I due to the inability to form synaptonemal complexes [ 86 , 142 ].…”

Section: Monogenic Forms Of Azoospermiamentioning

confidence: 99%

Genetics of Azoospermia

Cioppi

Rosta

Krausz

2021

IJMS

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Azoospermia affects 1% of men, and it can be due to: (i) hypothalamic-pituitary dysfunction, (ii) primary quantitative spermatogenic disturbances, (iii) urogenital duct obstruction. Known genetic factors contribute to all these categories, and genetic testing is part of the routine diagnostic workup of azoospermic men. The diagnostic yield of genetic tests in azoospermia is different in the different etiological categories, with the highest in Congenital Bilateral Absence of Vas Deferens (90%) and the lowest in Non-Obstructive Azoospermia (NOA) due to primary testicular failure (~30%). Whole-Exome Sequencing allowed the discovery of an increasing number of monogenic defects of NOA with a current list of 38 candidate genes. These genes are of potential clinical relevance for future gene panel-based screening. We classified these genes according to the associated-testicular histology underlying the NOA phenotype. The validation and the discovery of novel NOA genes will radically improve patient management. Interestingly, approximately 37% of candidate genes are shared in human male and female gonadal failure, implying that genetic counselling should be extended also to female family members of NOA patients.

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“…No structure of BRC-DMC1 exists. DMC1 behaves somewhat differently from the other recombinases 17 because it has higher propensity to form rings rather than filaments [43][44][45][46] . It was crystallized several times as an octamer, either in its full-length or its N-terminally truncated form.…”

Section: Introductionmentioning

confidence: 99%

DMC1 and RAD51 bind FxxA and FxPP motifs of BRCA2 via two separate interfaces

Miron,

Legrand,

van Rossum-Fikkert

et al. 2023

Preprint

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In vertebrates, the BRCA2 protein is essential for meiotic and somatic homologous recombination (HR) due to its interaction with RAD51 and DMC1 strand exchange proteins (recombinases). The interaction is mediated by FxxA and FxPP motifs, whose defining feature is the invariant phenylalanine. The FxxA motifs, present in the eight BRC repeats in the central region of BRCA2, compete with the FxxA motif of the linker region of RAD51 that is responsible for recombinase self-oligomerization. In vitro, BRCs disrupt RAD51 nucleoprotein filaments, but they are essential for RAD51 function in the context of the full-length BRCA2 protein. The role of the FxPP motifs is poorly studied but they also contribute to BRCA2 function in cells. In particular, the C-terminal TR2/CTRB domain of BRCA2, which contains an FxPP motif, is required for stabilization of RAD51 filament and replication fork protection. We recently found that deletion of the BRCA2 PhePP domain, which contains another FxPP motif, disrupts DMC1 but not RAD51 function in meiosis. Here we provide a mechanistic explanation for this phenotype by solving the crystal structure of the complex between DMC1 and the PhePP domain of BRCA2. Our structure reveals that, despite sequence similarity, the A-motifs (FxxA) and P-motifs (FxPP) bind to distinct and contiguous sites on the recombinases. The PhePP P-motif binding site is mostly located at the ATPase domain surface of a DMC1 monomer, but also extends to the linker region of the adjacent monomer, thus engaging two adjacent protomers in the DMC1 oligomer. Our structural analysis provides a mechanism explaining how PhePP favors the formation of the DMC1 nucleoprotein filament and stabilizes it. It corroborates and explains the stabilizing effect of the P-motif from BRCA2 TR2/CTRB on RAD51.

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Structure of a filament of stacked octamers of human DMC1 recombinase

Cited by 7 publications

References 49 publications

desynaptic5 carries a spontaneous semi-dominant mutation affecting Disrupted Meiotic cDNA 1 in barley

desynaptic5 carries a spontaneous semi-dominant mutation affecting Disrupted Meiotic cDNA 1 in barley

Genetics of Azoospermia

DMC1 and RAD51 bind FxxA and FxPP motifs of BRCA2 via two separate interfaces

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