The Cdc14 Phosphatase Controls Resolution of Recombination Intermediates and Crossover Formation during Meiosis

Abstract

Meiotic defects derived from incorrect DNA repair during gametogenesis can lead to mutations, aneuploidies and infertility. The coordinated resolution of meiotic recombination intermediates is required for crossover formation, ultimately necessary for the accurate completion of both rounds of chromosome segregation. Numerous master kinases orchestrate the correct assembly and activity of the repair machinery. Although much less is known, the reversal of phosphorylation events in meiosis must also be key to coordinate the timing and functionality of repair enzymes. Cdc14 is a crucial phosphatase required for the dephosphorylation of multiple CDK1 targets in many eukaryotes. Mutations that inactivate this phosphatase lead to meiotic failure, but until now it was unknown if Cdc14 plays a direct role in meiotic recombination. Here, we show that the elimination of Cdc14 leads to severe defects in the processing and resolution of recombination intermediates, causing a drastic depletion in crossovers when other repair pathways are compromised. We also show that Cdc14 is required for the correct activity and localization of the Holliday Junction resolvase Yen1/GEN1. We reveal that Cdc14 regulates Yen1 activity from meiosis I onwards, and this function is essential for crossover resolution in the absence of other repair pathways. We also demonstrate that Cdc14 and Yen1 are required to safeguard sister chromatid segregation during the second meiotic division, a late action that is independent of the earlier role in crossover formation. Thus, this work uncovers previously undescribed functions of the evolutionary conserved Cdc14 phosphatase in the regulation of meiotic recombination.

Epidemiology of Δ8THC-Related Carcinogenesis in USA: A Panel Regression and Causal Inferential Study

“…Both single-and double-stranded breaks (SSB and DSB) are a common feature of cell karyotype studies after cannabis exposure [7][8][9][10]12,13,99]. It therefore becomes important in the present context to note that the epigenome plays an often determinative role in influencing or selecting the site of DNA breakage generally [118][119][120][121][122][123][124][125][126][127][128][129][130][131], during meiotic crossing over [132][133][134][135][136][137][138][139], in the immune gene hypervariable region [140][141][142][143][144][145][146], and in oncogenic pathways [120,123,124,[147][148][149][150][151][152][153]…”

Cyclins and CDKs in the regulation of meiosis-specific events

“…Yen1 SSE has been widely studied in S. cerevisiae . During meiotic cell cycle, in sharp contrast to Mms4, CDK (Cdc28)-mediated phosphorylation of Yen1 restrains its function until anaphase II when it acts as an additional back-up system for late persistent JMs ( Matos et al, 2011 ; Alonso-Ramos et al, 2021 ). yen1 deletion mutant does not present obvious defects in chromosome segregations under unchallenged conditions, but additional deletion of other repair pathways as Sgs1 and Mus81-Mms4 results in defective JM resolution and abnormal anaphase I and II segregations, that unveils the safeguard activity of Yen1 ( Matos et al, 2011 ; Alonso-Ramos et al, 2021 ).…”

“…During meiotic cell cycle, in sharp contrast to Mms4, CDK (Cdc28)-mediated phosphorylation of Yen1 restrains its function until anaphase II when it acts as an additional back-up system for late persistent JMs ( Matos et al, 2011 ; Alonso-Ramos et al, 2021 ). yen1 deletion mutant does not present obvious defects in chromosome segregations under unchallenged conditions, but additional deletion of other repair pathways as Sgs1 and Mus81-Mms4 results in defective JM resolution and abnormal anaphase I and II segregations, that unveils the safeguard activity of Yen1 ( Matos et al, 2011 ; Alonso-Ramos et al, 2021 ). The specific mechanism of Yen1 dual phospho-regulation by Cdc28 and Cdc14 phosphatase was first elucidated in vegetative cells ( Blanco et al, 2014 ; Eissler et al, 2014 ; Garcia-Luis et al, 2014 ), but it has also been described in meiosis.…”

The N-Terminal Region of the Polo Kinase Cdc5 Is Required for Downregulation of the Meiotic Recombination Checkpoint

“…Cdc5 performs paramount roles in all these processes, highlighting the relevance of PLKs also during meiosis [6]. Cdc5 is required for exit from prophase I, triggering synaptonemal complex (SC) destruction and resolution of recombination intermediates [7][8][9]. Next, Cdc5 is also essential for meiotic chromosome segregation promoting removal of centromeric cohesion by Rec8 phosphorylation and establishing coorientation of sister kinetochores by triggering the nucleolar release of Lsr4/Csm1 and monopolin association to kinetochores [10][11][12][13].…”