Spo11 and the Formation of DNA Double-Strand Breaks in Meiosis

Keeney, Scott

doi:10.1007/7050_2007_026

Cited by 311 publications

(371 citation statements)

References 237 publications

(378 reference statements)

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“…Gonadal dysgenesis in Atm mice was initially thought to be caused by defects in meiotic recombination (30,34), which is induced by DSBs generated by the SPO11 protein (49). Consistent with our results in mouse somatic cells, however, recent studies have shown that ATM is not required for meiotic recombination, like when Spo11 gene dosage is reduced (50), but rather, that ATM plays an important role in regulating DSB levels during meiosis (51).…”

Section: Discussionsupporting

confidence: 90%

Double-strand break repair by homologous recombination in primary mouse somatic cells requires BRCA1 but not the ATM kinase

Kass¹,

Helgadottir

Chen

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Homology-directed repair (HDR) is a critical pathway for the repair of DNA double-strand breaks (DSBs) in mammalian cells. Efficient HDR is thought to be crucial for maintenance of genomic integrity during organismal development and tumor suppression. However, most mammalian HDR studies have focused on transformed and immortalized cell lines. We report here the generation of a Direct Repeat (DR)-GFP reporter-based mouse model to study HDR in primary cell types derived from diverse lineages. Embryonic and adult fibroblasts from these mice as well as cells derived from mammary epithelium, ovary, and neonatal brain were observed to undergo HDR at I-SceI endonuclease-induced DSBs at similar frequencies. When the DR-GFP reporter was crossed into mice carrying a hypomorphic mutation in the breast cancer susceptibility gene Brca1, a significant reduction in HDR was detected, showing that BRCA1 is critical for HDR in somatic cell types. Consistent with an HDR defect, Brca1 mutant mice are highly sensitive to the cross-linking agent mitomycin C. By contrast, loss of the DSB signaling ataxia telangiectasia-mutated (ATM) kinase did not significantly alter HDR levels, indicating that ATM is dispensable for HDR. Notably, chemical inhibition of ATM interfered with HDR. The DR-GFP mouse provides a powerful tool for dissecting the genetic requirements of HDR in a diverse array of somatic cell types in a normal, nontransformed cellular milieu.

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Section: Discussionsupporting

confidence: 90%

Double-strand break repair by homologous recombination in primary mouse somatic cells requires BRCA1 but not the ATM kinase

Kass¹,

Helgadottir

Chen

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…Perhaps because of this divergence, we have been unable to identify clear homologs of these proteins in most organisms other than those related to S. cerevisiae. Similar divergence is seen for the other meiosis-regulated DSB proteins Jiao et al 2002;Henderson et al 2006;Keeney 2007), but this feature is not unique to the DSB proteins, as it has been observed that meiotic recombination proteins in general tend to be among the most rapidly diverging groups of proteins in the cell (see Ramesh et al 2005;Richard et al 2005). …”

Section: Amino Acid Sequence Alignments Of Highly Diverged Yeast Mei4supporting

confidence: 59%

“…Rec114 and Mei4 are highly divergent. For example, in the very closely related species S. cerevisiae and S. paradoxus, Mei4 and Rec114 homologs share only 84.1% and 73.4% amino acid identity, respectively Keeney 2007). In contrast, the nucleotide sequence across all coding regions in these species is >88% identical and ∼65% of proteins have ≥90% amino acid identity (Cliften et al 2001).…”

Section: Amino Acid Sequence Alignments Of Highly Diverged Yeast Mei4mentioning

confidence: 99%

“…Meiotic recombination is initiated by DNA doublestrand breaks (DSBs) formed by the evolutionarily conserved Spo11 protein, which cuts DNA through a topoisomerase-like reaction (reviewed in Keeney 2001;Keeney 2007). However, Spo11 alone is not sufficient for DSB formation in vivo: in budding yeast at least nine other proteins are also required to generate a DSB (Keeney 2001;Keeney 2007).…”

Section: Introductionmentioning

confidence: 99%

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Interactions between Mei4, Rec114, and other proteins required for meiotic DNA double-strand break formation in Saccharomyces cerevisiae

et al. 2007

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In most sexually reproducing organisms, meiotic recombination is initiated by DNA double-strand breaks (DSBs) formed by the Spo11 protein. In budding yeast, nine other proteins are also required for DSB formation, but roles of these proteins and interactions among them are poorly understood. We report here further studies of the behaviors of these proteins. Consistent with other studies, we find that Mei4 and Rec114 bind to chromosomes from leptonema through early pachynema. Both proteins showed only limited colocalization with the meiotic cohesin subunit Rec8, suggesting that Mei4 and Rec114 associated preferentially with chromatin loops. Rec114 localization was independent of other DSB factors, but Mei4 localization was strongly dependent on Rec114 and Mer2. Systematic deletion analysis identified protein regions important for a previously described two-hybrid interaction between Mei4 and Rec114. We also report functional characterization of a previously misannotated 5′ coding exon of REC102. Sequences encoded in this exon are essential for DSB formation and for Rec102 interaction with Rec104, Spo11, Rec114, and Mei4. Finally, we also examined genetic requirements for a set of previously described two-hybrid interactions that can be detected only when the reporter strain is induced to enter meiosis. This analysis reveals new functional dependencies for interactions among the DSB proteins. Taken together, these studies support the view that Mei4, Rec114, and Mer2 make up a functional subgroup that is distinct from other subgroups of the DSB proteins: Spo11-Ski8, Rec102-Rec104, and Mre11-Rad50-Xrs2. These studies also suggest that an essential function of Rec102 and Rec104 is to connect Mei4 and Rec114 to Spo11.

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“…2 A). SPO11은 고세균 Topoisomerase VI의 상동체이며, 활성 중심 부위인 tyrosine 잔기 ester 전이 반응에 의해 DNA 가닥을 절단한다 (Keeney et al 1997;Keeney 2008). 또한 SPO11은 DNA 절단 후 DNA와 공유 결합된 상태로 남아있다 (Keeney et al 1997;Keeney, 2008 (Fig.…”

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Current status and prospects of the meiosis-specific function of recombinase in plants

et al. 2018

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Meiosis is a specialized cell division, essential in most reproducing organisms to halve the number of chromosomes, thereby enabling the restoration of ploidy levels during fertilization. A key step in meiosis is homologous recombination, which promotes homologous pairing and generates crossovers (COs) to connect homologous chromosomes until their separation at anaphase I. These CO sites, seen cytologically as chiasmata, represent a reciprocal exchange of genetic information between two homologous non-sister chromatids. RAD51, the eukaryotic homolog of the bacterial RecA recombinase, plays a central role in homologous recombination (HR) in yeast and animals. Loss of RAD51 function causes lethality in the flowering plant, Arabidopsis thaliana, suggesting that RAD51 has a meiotic stage-specific function that is different from homologous pairing activity.

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Spo11 and the Formation of DNA Double-Strand Breaks in Meiosis

Cited by 311 publications

References 237 publications

Double-strand break repair by homologous recombination in primary mouse somatic cells requires BRCA1 but not the ATM kinase

Double-strand break repair by homologous recombination in primary mouse somatic cells requires BRCA1 but not the ATM kinase

Interactions between Mei4, Rec114, and other proteins required for meiotic DNA double-strand break formation in Saccharomyces cerevisiae

Current status and prospects of the meiosis-specific function of recombinase in plants

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