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Research Project: Intervention Strategies to Support the Global Control and Eradication of Foot-and-Mouth Disease Virus (FMDV)

Location: Foreign Animal Disease Research

Title: Mek1 coordinates meiotic progression with DNA break repair by directly phosphorylating and inhibiting the yeast pachytene exit regulator Ndt80

item CHEN, XIANGYU - Stony Brook University
item GAGLIONE, ROBERT - Stony Brook University
item LEONG, TREVOR - Stony Brook University
item BEDNOR, LAUREN - Stony Brook University
item De Los Santos, Teresa
item LUK, ED - Stony Brook University
item AIROLA, MICHAEL - Stony Brook University
item HOLLINGSWORTH, NANCY - Stony Brook University

Submitted to: PLoS Genetics
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 11/3/2018
Publication Date: 11/29/2018
Citation: Chen, X., Gaglione, R., Leong, T., Bednor, L., De los Santos, T.B., Luk, E., Airola, M., Hollingsworth, N.M. 2018. Mek1 coordinates meiotic progression with DNA break repair by directly phosphorylating and inhibiting the yeast pachytene exit regulator Ndt80. PLoS Genetics.

Interpretive Summary: Dr. Hollingsworth (Stony Brook University) is a pioneer in the study of meiotic chromosome segregation. Dr. de los Santos (ARS, USDA) did her doctoral work in her lab. Data collected during her doctoral studies were further analyzed and extended resulting in the current discoveries that are submitted for publication in Plos Genetics. The authors discovered the molecular basis by which the Mek1 protein controls the function of Ndt80 a transcription factor critical for the completion of the meiotic cell division in yeast.

Technical 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. To allow time for these breaks to be processed into interhomolog crossovers, meiosis-specific modifications to the DSB-induced DNA damage response, called the meiotic recombination checkpoint, delay entry into Meiosis I until all of 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 is unknown. This work demonstrates that Mek1 indirectly provides a readout for the number of DSBs during meiosis, by binding to Ndt80 and phosphorylating multiple sites thus inhibiting DNA binding and preventing its function as a transcriptional activator. Repair of DSBs by recombination reduces Mek1 activity below a threshold that allows dephosphorylation of Ndt80 to activate its transcription factor activity. Ndt80 binds to its own promoter and the promoters of target genes to enable expression of genes necessary to complete recombination, exit prophase and progress into the first meiotic division.