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. 2011 Apr-Jun;5(2):134-40.
doi: 10.4161/fly.5.2.14767. Epub 2011 Apr 1.

Meiotic checkpoints and the interchromosomal effect on crossing over in Drosophila females

Eric F Joyce  1 , Kim S McKim
Affiliations

Meiotic checkpoints and the interchromosomal effect on crossing over in Drosophila females

Eric F Joyce et al. Fly (Austin). 2011 Apr-Jun.

Abstract

During prophase of meiosis I, genetic recombination is initiated with a Spo11-dependent DNA double-strand break (DSB). Repair of these DSBs can generate crossovers, which become chiasmata and are important for the process of chromosome segregation. To ensure at least one chiasma per homologous pair of chromosomes, the number and distribution of crossovers is regulated. One system contributing to the distribution of crossovers is the pachytene checkpoint, which requires the conserved gene pch2 that encodes an AAA+ATPase family member. Pch2-dependent pachytene checkpoint function causes delays in pachytene progression when there are defects in processes required for crossover formation, such as mutations in DSB-repair genes and when there are defects in the structure of the meiotic chromosome axis. Thus, the pachytene checkpoint appears to monitor events leading up to the generation of crossovers. Interestingly, heterozygous chromosome rearrangements cause Pch2-dependent pachytene delays and as little as two breaks in the continuity of the paired chromosome axes are sufficient to evoke checkpoint activity. These chromosome rearrangements also cause an interchromosomal effect on recombination whereby crossing over is suppressed between the affected chromosomes but is increased between the normal chromosome pairs. We have shown that this phenomenon is also due to pachytene checkpoint activity.

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Figures

Figure 1
Figure 1
Meiotic DSB repair pathway in Drosophila females. The Drosophila genes names are shown along with human homologs in parentheses. The SC (shown in green) forms independently of DSBs. The DSB repair genes are required for repair of all DSBs and the generation of both crossovers and noncrossover products. The suggestion in the figure, although not proven, is that the precondition genes enable the formation of an intermediate that can be resolved into a crossover. A Holliday junction is suggested in the Figure but other structures, such as an unligated intermediate, are possible. In the absence of the precondition genes, intermediates are made that can only become noncrossovers, possibly by an SDSA mechanism. The exchange genes resolve the precondition gene-dependent intermediates as crossovers. There must also be a pathway to get out of this intermediate as a noncrossover (shown by the “?”) to resolve recombination intermediates in exchange mutants.
Figure 2
Figure 2
Organization of the Drosophila Germarium. Region 1 is where the mitotic divisions occur to generate 16 cell cysts. In region 2a, each 16-cell cyst has two cells (pro-oocytes) in zygotene or pachytene. Oocytes can be identified by the SC (green), or cytoplasmic markers such as ORB (blue), although the SC is the most reliable and earliest visible marker. DSBs are generated in region 2a and can be detected by an antibody to phosphorylated H2AV (not shown). In region 2b and 3, the decision is made for one of the pro-oocytes to become a nurse cell. Pachytene checkpoint activity can be detected as delays in either the appearance and persistence of phosphorylated H2AV, the presence of two pro-oocytes in region 3 cysts or the persistence of Pch2 expression.
Figure 3
Figure 3
Effect of inversions on pachytene delays. Pachytene delays are observed when chromosome rearrangements are heterozygous. The inverted part of the chromosome is shown in yellow. A pachytene delay occurs in c(3)G mutants and, therefore, do not depend on synapsis. The misalignment of two homologous chromosomes may be detected by a synapsis-independent pairing mechanism that may lead to defects in the axial structure of the chromosomes.
Figure 4
Figure 4
Model for how the pachytene checkpoint regulates pachytene. A crossover determination phase allows the distribution and level of exchange per chromosome to be established, prior to and independent of DSB repair. PCH2 activity may regulate the crossover determination phase and restrict this time frame to the zygotene and early pachytene stages of prophase. (A) In wild-type, PCH2 is normally degraded prior to mid-pachytene, which turns off the checkpoint signal, ends the crossover determination phase. (B) Defects in DSB repair proteins or in the axis structure of the homologs cause Sir2 to prolong PCH2 activity, which extends the crossover determination phase and increases the chance of DSBs becoming crossovers. The increase in the number of crossovers could be due to the lengthening of this phase or altering the regulation of proteins that affect crossover formation.
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