Phospho-Regulation of Meiotic Prophase

Kar, Funda M; Hochwagen, Andreas

doi:10.3389/fcell.2021.667073

Cited by 15 publications

(13 citation statements)

References 291 publications

(505 reference statements)

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“…Mutation of the DSB-1 ATM/ATR consensus site serines to alanine leads to increased DSB numbers in a wild-type background, and rescues the DSB loss phenotypes of pph-4.1 and dsb-2 mutants. This finding may illuminate a more straightforward mechanism of action compared to the yeast homolog Rec114, in which mutation of ATM/ATR consensus sites show contrasting results on DSB number depending on the assay used ( Kar and Hochwagen, 2021 ; discussed in Lukaszewicz et al, 2018 ). Based on our results, the most straightforward model is that PPH-4.1 dephosphorylates DSB-1 to promote DSBs, whereas break-activated ATL-1 phosphorylates DSB-1 to prevent excess DSB production, and this phosphoregulation circuit ensures termination of DSB production only after sufficient numbers of DSBs are generated.…”

Section: Discussionmentioning

confidence: 90%

Phosphoregulation of DSB-1 mediates control of meiotic double-strand break activity

Guo

Stamper

Sato-Carlton

et al. 2022

eLife

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In the first meiotic cell division, proper segregation of chromosomes in most organisms depends on chiasmata, exchanges of continuity between homologous chromosomes that originate from the repair of programmed double-strand breaks (DSBs) catalyzed by the Spo11 endonuclease. Since DSBs can lead to irreparable damage in germ cells, while chromosomes lacking DSBs also lack chiasmata, the number of DSBs must be carefully regulated to be neither too high nor too low. Here, we show that in Caenorhabditis elegans, meiotic DSB levels are controlled by the phosphoregulation of DSB-1, a homolog of the yeast Spo11 cofactor Rec114, by the opposing activities of PP4PPH-4.1 phosphatase and ATRATL-1 kinase. Increased DSB-1 phosphorylation in pph-4.1 mutants correlates with reduction in DSB formation, while prevention of DSB-1 phosphorylation drastically increases the number of meiotic DSBs both in pph-4.1 mutants and in the wild-type background. C. elegans and its close relatives also possess a diverged paralog of DSB-1, called DSB-2, and loss of dsb-2 is known to reduce DSB formation in oocytes with increasing age. We show that the proportion of the phosphorylated, and thus inactivated, form of DSB-1 increases with age and upon loss of DSB-2, while non-phosphorylatable DSB-1 rescues the age-dependent decrease in DSBs in dsb-2 mutants. These results suggest that DSB-2 evolved in part to compensate for the inactivation of DSB-1 through phosphorylation, to maintain levels of DSBs in older animals. Our work shows that PP4PPH-4.1, ATRATL-1, and DSB-2 act in concert with DSB-1 to promote optimal DSB levels throughout the reproductive lifespan.

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Section: Discussionmentioning

confidence: 90%

Phosphoregulation of DSB-1 mediates control of meiotic double-strand break activity

Guo

Stamper

Sato-Carlton

et al. 2022

eLife

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“…We speculate that this shift toward posttranslational signaling reflects the unique needs created by the programmed induction of nearly 200 DNA breaks. As protein modifications have the crucial potential to create spatially distinct and constrained signals, they are uniquely suitable to support the patterning of the meiotic recombination landscape and the creation of local or chromosome-wide dependencies in a shared nuclear environment, which is a key feature of meiotic recombination (Kar & Hochwagen, 2021).…”

Section: Discussionmentioning

confidence: 99%

“…Available data indicate a prominent role for the canonical DNA-damage sensor kinases ATR and ATM, although the extent to which the two kinases are linked to the control of meiotic processes may vary between organisms (Kar & Hochwagen, 2021). In the budding yeast, Saccharomyces cerevisiae , the homologues of ATR and ATM, Mec1 and Tel1, respectively, and the downstream CHK2-like effector kinase Mek1 regulate a large number of meiotic processes, including DNA break formation and repair, chromosome pairing, and meiotic cell-cycle progression (Kar & Hochwagen, 2021). Targeted studies in yeast have identified relevant DNA break-dependent phosphorylation events for several of these processes, including control of break levels (Carballo et al, 2013), suppression of sister-chromatid recombination (Callender et al, 2016; Carballo et al, 2008; Niu et al, 2009), crossover formation (Chen et al, 2015; He et al, 2020; Woo et al, 2020), centromere uncoupling (Falk et al, 2010), and control of meiotic cell-cycle progression (Chen et al, 2018; Penedos et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

Meiotic DNA breaks activate a streamlined phospho-signaling response that largely avoids protein level changes

Kar

Vogel

Hochwagen

2022

Preprint

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Meiotic cells introduce a large number of programmed DNA breaks into their genome to stimulate meiotic recombination and ensure controlled chromosome inheritance and fertility. An intricate checkpoint network involving key kinases and phosphatases coordinates the repair of these DNA breaks during meiosis, but the precise DNA break-dependent phosphorylation targets remain poorly understood. It is also unknown whether meiotic DNA breaks change gene expression akin to the canonical DNA-damage response. To address these questions, we analyzed the meiotic DNA break response in Saccharomyces cerevisiae using multiple systems-level approaches. We identified 332 DNA break-dependent phosphorylation sites, vastly expanding the number of known DNA break-dependent phosphorylation events during meiotic prophase. Only about half of these events occurred in recognition motifs for the known meiotic checkpoint kinases Mec1 (ATR), Tel1 (ATM) and Mek1 (CHK2), suggesting that additional kinases contribute to the meiotic DNA break response. Surprisingly, the numerous changes in phosphorylation were accompanied by very few changes in protein levels despite a clearly detectable transcriptional response. To explain this dichotomy, we show that meiotic entry lowers the expression baseline of many mRNAs enough so that subsequent break-dependent mRNA production has no measurable effects on the largely stable proteome.

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“…We are only beginning to understand the signaling pathways that connect meiotic DNA break formation to DNA repair and other meiotic processes. Available data indicate a prominent role for the canonical DNA-damage sensor kinases ATR and ATM, although the extent to which the two kinases are linked to the control of meiotic processes may vary between organisms ( Kar & Hochwagen, 2021 ). In the budding yeast, Saccharomyces cerevisiae , the homologues of ATR and ATM, Mec1, and Tel1, respectively, and the downstream CHK2-like effector kinase Mek1 regulate a large number of meiotic processes, including DNA break formation and repair, chromosome pairing, and meiotic cell-cycle progression ( Kar & Hochwagen, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

Meiotic DNA breaks activate a streamlined phospho-signaling response that largely avoids protein-level changes

2022

Self Cite

View full text Add to dashboard Cite

Meiotic cells introduce a numerous programmed DNA breaks into their genome to stimulate meiotic recombination and ensure controlled chromosome inheritance and fertility. A checkpoint network involving key kinases and phosphatases coordinates the repair of these DNA breaks, but the precise phosphorylation targets remain poorly understood. It is also unknown whether meiotic DNA breaks change gene expression akin to the canonical DNA-damage response. To address these questions, we analyzed the meiotic DNA break response in Saccharomyces cerevisiae using multiple systems-level approaches. We identified 332 DNA break–dependent phosphorylation sites, vastly expanding the number of known events during meiotic prophase. Less than half of these events occurred in recognition motifs for the known meiotic checkpoint kinases Mec1 (ATR), Tel1 (ATM), and Mek1 (CHK2), suggesting that additional kinases contribute to the meiotic DNA-break response. We detected a clear transcriptional program but detected only very few changes in protein levels. We attribute this dichotomy to a decrease in transcript levels after meiotic entry that dampens the effects of break-induced transcription sufficiently to cause only minimal changes in the meiotic proteome.

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Phospho-Regulation of Meiotic Prophase

Cited by 15 publications

References 291 publications

Phosphoregulation of DSB-1 mediates control of meiotic double-strand break activity

Phosphoregulation of DSB-1 mediates control of meiotic double-strand break activity

Meiotic DNA breaks activate a streamlined phospho-signaling response that largely avoids protein level changes

Meiotic DNA breaks activate a streamlined phospho-signaling response that largely avoids protein-level changes

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