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Review
. 2014 Oct 1;6(10):a016675.
doi: 10.1101/cshperspect.a016675.

The meiotic checkpoint network: step-by-step through meiotic prophase

Vijayalakshmi V Subramanian  1 , Andreas Hochwagen  1
Affiliations
Review

The meiotic checkpoint network: step-by-step through meiotic prophase

"V体育官网" Vijayalakshmi V Subramanian et al. Cold Spring Harb Perspect Biol. .

Abstract

The generation of haploid gametes by meiosis is a highly conserved process for sexually reproducing organisms that, in almost all cases, involves the extensive breakage of chromosomes. These chromosome breaks occur during meiotic prophase and are essential for meiotic recombination as well as the subsequent segregation of homologous chromosomes. However, their formation and repair must be carefully monitored and choreographed with nuclear dynamics and the cell division program to avoid the creation of aberrant chromosomes and defective gametes VSports手机版. It is becoming increasingly clear that an intricate checkpoint-signaling network related to the canonical DNA damage response is deeply interwoven with the meiotic program and preserves order during meiotic prophase. This meiotic checkpoint network (MCN) creates a wide range of dependent relationships controlling chromosome movement, chromosome pairing, chromatin structure, and double-strand break (DSB) repair. In this review, we summarize our current understanding of the MCN. We discuss commonalities and differences in different experimental systems, with a particular emphasis on the emerging design principles that control and limit cross talk between signals to ultimately ensure the faithful inheritance of chromosomes by the next generation. .

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Figures

Figure 1.
Figure 1.
A crossover establishes a physical link between homologous chromosomes. (A) Schematic of a pair of homologous chromosomes (red and purple). The replicated sister chromatids are held together by cohesion (green rings). (B) A crossover between homologous chromosomes, in conjunction with cohesion distal to the crossover site, establishes a physical connection between them. (C) A crossover allows homologous chromosomes to orient properly on the meiotic spindle (gray lines).
Figure 2.
Figure 2.
Meiotic DNA replication and DSB repair events occur concomitantly with chromosome structural morphogenes. Schematic of DNA metabolism (A), and chromosomal organization events (B) during meiotic prophase. The homologous chromosomes replicate during premeiotic S phase. At leptonema, the DSBs are initiated, whereas telomeres of the chromosomes become tethered to the nuclear envelope and the meiotic chromosomes assume a bouquet conformation (in most organisms). Synapsis (depicted by gray lines) between homologous chromosome pairs is thought to initiate at sites of crossover repair in zygonema. By pachynema the homologous chromosomes are fully synapsed and the crossover-designated repair is at the double-Holliday junction intermediate stage. The synaptonemal complex disassembles at diplonema to reveal the crossover sites between the homologous chromosomes.
Figure 3.
Figure 3.
Dependent relationships established by the MCN. The meiotic checkpoint network creates a web of dependencies to promote sequential progression of meiotic events (A), or prevent meiotic progression in the face of defective repair or synapsis (B). Dashed lines and arrows indicate a modulation in activity.
Figure 4.
Figure 4.
The meiotic checkpoint network integrates signal to the appropriate response. (A) Stalled replication forks prevent DSB formation via several mechanisms in S. cerevisiae. Mec1 regulates transcription of SPO11 and recruitment of Rec114 to the meiotic chromosomes, whereas the downstream Rad53 kinase controls phosphorylation of Mer2 by regulating the activity of DDK kinase. (B) MCN regulates resection. Both Tel1 and Mec1 kinases activate Sae2 for DSB end resection to generate 3′ ssDNA overhangs. The MCN also prevents hyperresection of break ends. (C) Mec1/Tel1 kinases promote IH bias via phosphorylation of Hop1, which in turn leads to recruitment, dimerization, and activation of Mek1 kinase. Regulation of Rad54 activity by Mek1 inhibits IS repair thus promoting IH bias. (D) In Drosophila, the MCN negatively regulates NHK-1 kinase. NHK-1 kinase controls condensation of the oocyte chromatin and also allows its release from the nuclear envelope on completion of DSB repair. (E) Unsynapsed chromatin in mouse recruits ATR via HORMAD1/2. ATR facilitates phosphorylation of H2AFX that spreads into the chromatin loops and recruits silencing factors. (F) MCN regulates exit from meiotic prophase by controlling the expression and localization of Ndt80 transcription factor as well as by inhibiting CDK kinase. Cdc5 kinase relieves inhibition of Ndt80 by the MCN in a feedforward loop to allow rapid exit from prophase.
Figure 5.
Figure 5.
Meiotic chromosome spread from mouse spermatocyte in pachynema depicting MSCI. The XY pair manifests as the sex body (white arrowhead) and is enriched for ATR (red). SCP3 (green) marks the axes of synapsed and unsynapsed chromosomes, DNA is in blue. (Image courtesy of Sarai Pacheco and Ignasi Roig.)
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References

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