Genetic dissection of crossover mutants defines discrete intermediates in mouse meiosis

Premkumar, Tolkappiyan; Paniker, Lakshmi; Kang, Rhea; Biot, Mathilde; Humphrey, Ericka; Destain, Honorine; Ferranti, Isabella; Okulate, Iyinyeoluwa; Nguyen, Holly; Kilaru, Vindhya; Frasca, Melissa; Chakraborty, Parijat; Cole, Francesca

doi:10.1101/2022.08.10.503530

Cited by 2 publications

(2 citation statements)

References 80 publications

(258 reference statements)

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“…At designated crossover sites, stabilization of MutSγ by RNF212, RNF212B, and HEI10 enables formation of double-Holliday junctions. An endonuclease-independent function of MutLγ is recently implicated in this step 63 .…”

Section: Sexual Dimorphismmentioning

confidence: 99%

Distinct and interdependent functions of three RING proteins regulate recombination during mammalian meiosis

Ito,

Yun,

Kulkarni

et al. 2023

Preprint

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SUMMARYCrossing-over between homologous chromosomes is essential for accurate segregation during meiosis. In mammals, factors required for crossing over include RNF212 and HEI10, RING-finger domain proteins implicated in modification by SUMO and ubiquitin, respectively. Here we show that a third RING protein, RNF212B, is essential for crossing over in mouse and characterize its relationships with RNF212 and HEI10. Mutant analysis indicates that, analogous to RNF212, RNF212B regulates recombination occurring in the context of synapsed chromosomes by stabilizing pro-crossover factors, regulating the progression of recombination, and enabling the differentiation and maturation of crossover-specific recombination complexes. Also, like RNF212, RNF212B localizes between synapsed chromosomes, initially as numerous foci along synaptonemal complexes (SCs) before undergoing HEI10-dependent redistribution to accumulate at prospective crossover sites. Despite these similarities, accumulation of RNF212B at nascent crossover sites is much greater than RNF212 and occurs earlier, coincident with the appearance of HEI10 foci, implicating concerted action of RNF212B and HEI10 in the differentiation of crossover sites. RNF212B localization also shows greater dependence on DNA double-strand breaks and SC formation than RNF212. Together, our analysis delineates three distinct but interdependent RING proteins that regulate meiotic recombination by integrating signals from DSBs, synapsis, the cell-cycle, and developing crossover sites.

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Section: Sexual Dimorphismmentioning

confidence: 99%

Distinct and interdependent functions of three RING proteins regulate recombination during mammalian meiosis

Ito,

Yun,

Kulkarni

et al. 2023

Preprint

View full text Add to dashboard Cite

show abstract

“…In this model, nicks maintained at the ends of synthesis tracts could direct biased and asymmetric cleavage of the dHJ by recruiting a nickbinding protein that acts in the resolution mechanism. Analysis of recombination events in the mouse has also led to a model that nicked dHJs are precursors to meiotic crossovers [45]. These studies and recent biochemical studies have led to proposals that Mlh1-Mlh3 interact with Exo1, Msh4-Msh5, and the DNA polymerase processivity factor PCNA to resolve dHJs in a biased fashion to form crossovers [46][47][48].…”

Section: Introductionmentioning

confidence: 99%

Exo1 protects DNA nicks from ligation to promote crossover formation during meiosis

et al. 2023

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In most sexually reproducing organisms crossing over between chromosome homologs during meiosis is essential to produce haploid gametes. Most crossovers that form in meiosis in budding yeast result from the biased resolution of double Holliday junction (dHJ) intermediates. This dHJ resolution step involves the actions of Rad2/XPG family nuclease Exo1 and the Mlh1-Mlh3 mismatch repair endonuclease. Here, we provide genetic evidence in baker’s yeast that Exo1 promotes meiotic crossing over by protecting DNA nicks from ligation. We found that structural elements in Exo1 that interact with DNA, such as those required for the bending of DNA during nick/flap recognition, are critical for its role in crossing over. Consistent with these observations, meiotic expression of the Rad2/XPG family member Rad27 partially rescued the crossover defect in exo1 null mutants, and meiotic overexpression of Cdc9 ligase reduced the crossover levels of exo1 DNA-binding mutants to levels that approached the exo1 null. In addition, our work identified a role for Exo1 in crossover interference. Together, these studies provide experimental evidence for Exo1-protected nicks being critical for the formation of meiotic crossovers and their distribution.

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Genetic dissection of crossover mutants defines discrete intermediates in mouse meiosis

Cited by 2 publications

References 80 publications

Distinct and interdependent functions of three RING proteins regulate recombination during mammalian meiosis

Distinct and interdependent functions of three RING proteins regulate recombination during mammalian meiosis

Exo1 protects DNA nicks from ligation to promote crossover formation during meiosis

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