Abstract
Meiotic recombination plays a critical role in sexual reproduction by creating crossovers between homologous chromosomes. These crossovers, along with sister chromatid cohesion, connect homologs to enable proper segregation at Meiosis I. Recombination is initiated by programmed double strand breaks (DSBs) at particular regions of the genome. The meiotic recombination checkpoint uses meiosis-specific modifications to the DSB-induced DNA damage response to provide time to convert these breaks into interhomolog crossovers by delaying entry into Meiosis I until the DSBs have been repaired. The meiosis-specific kinase, Mek1, is a key regulator of meiotic recombination pathway choice, as well as being required for the meiotic recombination checkpoint. The major target of this checkpoint is the meiosis-specific transcription factor, Ndt80, which is essential to express genes necessary for completion of recombination and meiotic progression. The molecular mechanism by which cells monitor meiotic DSB repair to allow entry into Meiosis I with unbroken chromosomes was unknown. Using genetic and biochemical approaches, this work demonstrates that in the presence of DSBs, activated Mek1 binds to Ndt80 and phosphorylates the transcription factor, thus inhibiting DNA binding and preventing Ndt80’s function as a transcriptional activator. Repair of DSBs by recombination reduces Mek1 activity, resulting in removal of the inhibitory Mek1 phosphates. Phosphorylation of Ndt80 by the meiosis-specific kinase, Ime2, then results in fully activated Ndt80. Ndt80 upregulates transcription of its own gene, as well as target genes, resulting in prophase exit and progression through meiosis.
Highlights
One of the most dangerous things for a cell is the occurrence of DNA double strand breaks (DSBs) in its chromosomes
How does the cell determine when sufficient double strand break repair has occurred? Our work provides a mechanistic explanation to this question
Mek1 interacts with a conserved sequence within a domain of Ndt80 that is required for meiotic recombination checkpoint arrest
Summary
One of the most dangerous things for a cell is the occurrence of DNA double strand breaks (DSBs) in its chromosomes. Failure to repair a DSB may result in a loss of genetic material and lethality. DSBs arise due to exogenous damage such as radiation, or endogenous errors such as stalled replication forks. Repair of DSBs by non-homologous end joining may lead to deletions, translocations or inversions, which can have adverse consequences such as cancer [1]. The most conservative way to repair a DSB is by homologous recombination, using the sister chromatid as the template. In mitotically dividing cells, homologous recombination mediated by the evolutionarily conserved recombinase, Rad, is biased towards using sister chromatids [2, 3]
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