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Localised negative feedback shapes genome-wide patterning of meiotic DNA breaks

ABSTRACT: Genetic diversity within sexually reproducing species arises via the formation and repair of programmed DNA double-strand breaks (DSBs) created by the evolutionarily conserved topoisomerase-like enzyme, Spo11. Because DSBs threaten genome stability, their formation is tightly regulated in both space and time. In S. cerevisiae, Tel1, the orthologue of mammalian Ataxia Telangiectasia Mutated (ATM) kinase, suppresses nearby DSB formation through local inhibition known as DSB interference. However, whether such local inhibition reshapes the genome-wide DSB landscape remains unclear. Here, we develop a quantitative simulation framework to model how Tel1-mediated feedback shapes Spo11-DSB formation across the yeast genome. We demonstrate that innate chromosome-specific DSB patterns, when combined with interference, generate complex, population-level redistribution of DSBs. We define the spatial range over which interference propagates and provide evidence that this regulatory mechanism requires Tel1 recruitment to DSBs via Xrs2 and Tel1 kinase activity. Although the pro-DSB factor Rec114 contributes to DSB regulation, mutation of potential Rec114 phosphorylation sites indicates that it is not an essential target of Tel1. Together, these findings demonstrate how localised negative feedback can drive broad-scale, emergent patterning of a fundamental genome-modifying process, with the potential in meiosis to influence recombination initiation and, consequently, genetic variation across generations.

ORGANISM(S): Saccharomyces cerevisiae

PROVIDER: GSE319316 | GEO | 2026/02/16

REPOSITORIES: GEO

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Budding yeast ATM/ATR contribute to meiotic double-strand-break (DSB) homeostasis by down-regulating Rec114, an essential component of the DSB-machinery

Project description:In most organisms, meiotic recombination begins with programmed DNA double strand break (DSB) formation by Spo11. Here, we present evidence that Tel1/Mec1, the budding yeast ATM/ATR, regulate DSB formation by phosphorylating Rec114, an essential Spo11-accessory protein. Analyses of a non-phosphorylatable- or phosphomimetic- alleles of rec114 revealed that DSB-dependent phosphorylation of Rec114 limited its association with DSB-hotspots resulting in reduction in DSB formation. Also observed were the impact of Rec114 phosphorylation on its homolog synapsis-associated removal from chromosomes and NDT80-dependent turnover. Specifically, we found that the synapsis- and NDT80-dependent Rec114 downregulation occurred later in the rec114 mutant with a reduced Spo11-catalysis, but earlier in the other with an enhanced catalysis, strongly implicating the existence of a feedback mechanism coupling the extent of Spo11-catalysis to Rec114 activity. Taken together, these observations suggest that three different mechanisms of down regulating Rec114 contribute to meiotic DSB homeostasis, a feedback mechanism to maintain the number of meiotic DSBs at the developmentally programmed level. 6 genome wide ChIPchip sets: 3 for meiotic DSB formation (Spo11-ChIP) and 3 for protein-DNA association (Rec114-ChIP), each for wild type and two mutants during meiosis (corresponding to the main Figure 3, as well as to Figures S3, S4, S5).

2013-06-01 | E-GEOD-43384 | biostudies-arrayexpress

Budding yeast ATM/ATR contribute to meiotic double-strand-break (DSB) homeostasis by down-regulating Rec114, an essential component of the DSB-machinery

2013-06-01 | GSE43384 | GEO

Tel1 is recruited at chromosomal loop/axis contact sites to modulate meiotic DNA double-strand breaks interference

Project description:During meiosis, the programmed formation of DNA double-strand breaks (DSBs) by Spo11, a conserved topoisomerase-like protein, initiates homologous recombination that leads to crossovers between homologous chromosomes, essential for accurate segregation and genome evolution. Because DSBs are a threat to genome integrity, their number, distribution and timing of formation are regulated during the meiotic program. In S. cerevisiae, DSB interference prevents the coincident formation of DSBs in neighboring hotspots through a Tel1/ATM dependent mechanism that remains unexplored. Here, we demonstrate that Tel1 is recruited to meiotic DSB hotspots in response to Spo11-DSB formation. We further show that Tel1 localizes to chromosomal axis sites in a DSB-dependent manner, thus supporting the tethered loop-axis complex (TLAC) model that postulates meiotic DSBs are formed within the chromosome axis environment. Tel1 recruitment to meiotic DSBs, DSB interference and the meiotic DNA damage checkpoint are dependent on both the Tel1-FATC domain and the C-terminal moiety of Xrs2, known to mediate Tel1-Xrs2 interaction in somatic cells. However, in a xrs2-K846/F847 mutant, DSBs interference remains functional despite Tel1 binding to DSB sites being significantly reduced and the Tel1-dependent DNA damage checkpoint abolished. Altogether, this work highlights the complex regulation of Tel1 multiple various functions in meiotic cells, and fine-tuning through interaction with Xrs2.

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Numerical and Spatial Patterning of Yeast Meiotic DNA Breaks by Tel1

Project description:The Spo11-generated double-strand breaks (DSBs) that initiate meiotic recombination are dangerous lesions that can disrupt genome integrity, so meiotic cells regulate their number, timing, and distribution. Here, we use Spo11-oligonucleotide complexes, a byproduct of DSB formation, to examine the contribution of the DNA damage-responsive kinase Tel1 (ortholog of mammalian ATM) to this regulation in Saccharomyces cerevisiae. A tel1Δ mutant had globally increased amounts of Spo11-oligonucleotide complexes and altered Spo11-oligonucleotide lengths, consistent with conserved roles for Tel1 in control of DSB number and processing. A kinase-dead tel1 mutation also increased Spo11-oligonucleotide levels, but mutating known Tel1 phosphotargets on Hop1 and Rec114 did not. Deep sequencing of Spo11 oligonucleotides from tel1Δ mutants demonstrated that Tel1 shapes the nonrandom DSB distribution in ways that are distinct but partially overlapping with previously described contributions of the recombination regulator Zip3. Finally, we uncover a context-dependent role for Tel1 in hotspot competition, in which an artificial DSB hotspot inhibits nearby hotspots. Evidence for Tel1-dependent competition involving strong natural hotspots is also provided.

2016-07-22 | GSE84696 | GEO

Numerical and Spatial Patterning of Yeast Meiotic DNA Breaks by Tel1

Project description:The Spo11-generated double-strand breaks (DSBs) that initiate meiotic recombination are dangerous lesions that can disrupt genome integrity, so meiotic cells regulate their number, timing, and distribution. Here, we use Spo11-oligonucleotide complexes, a byproduct of DSB formation, to examine the contribution of the DNA damage-responsive kinase Tel1 (ortholog of mammalian ATM) to this regulation in Saccharomyces cerevisiae. A tel1Î mutant had globally increased amounts of Spo11-oligonucleotide complexes and altered Spo11-oligonucleotide lengths, consistent with conserved roles for Tel1 in control of DSB number and processing. A kinase-dead tel1 mutation also increased Spo11-oligonucleotide levels, but mutating known Tel1 phosphotargets on Hop1 and Rec114 did not. Deep sequencing of Spo11 oligonucleotides from tel1Î mutants demonstrated that Tel1 shapes the nonrandom DSB distribution in ways that are distinct but partially overlapping with previously described contributions of the recombination regulator Zip3. Finally, we uncover a context-dependent role for Tel1 in hotspot competition, in which an artificial DSB hotspot inhibits nearby hotspots. Evidence for Tel1-dependent competition involving strong natural hotspots is also provided. Sixteen samples total: The first 12 are two biological replicate Spo11-oligo maps from each of the following: wild type and tel1 each collected at 4, 5, and 6 hours after meiotic induction; the next 4 are one biological replicate Spo11-oligo map from each of the following: wild type and tel1 bearing an artificial hotspot insertion either on Chr III or on Chr IX.

2016-07-22 | E-GEOD-84696 | biostudies-arrayexpress

Meiotic prophase length modulates Tel1-dependent DNA double-strand break interference

Project description:During meiosis, genetic recombination is initiated by the formation of many DNA double-strand breaks (DSBs) catalysed by the evolutionarily conserved topoisomerase-like enzyme, Spo11, in preferred genomic sites known as hotspots. DSB formation activates the Tel1/ATM DNA damage responsive (DDR) kinase, locally inhibiting Spo11 activity in adjacent hotspots via a process known as DSB interference. Intriguingly, in S. cerevisiae, over short genomic distances (<15 kb), Spo11 activity displays characteristics of concerted activity or clustering, wherein the frequency of DSB formation in adjacent hotspots is greater than expected by chance. We have proposed that clustering is caused by a limited number of sub-chromosomal domains becoming primed for DSB formation. Here, we provide evidence that DSB clustering is abolished when meiotic prophase timing is extended via deletion of the NDT80 transcription factor. We propose that extension of meiotic prophase enables most cells, and therefore most chromosomal domains within them, to reach an equilibrium state of similar Spo11-DSB potential, reducing the impact that priming has on estimates of coincident DSB formation. Consistent with this view, when Tel1 is absent but Ndt80 is present and thus cells are able to rapidly exit meiotic prophase, genome-wide maps of Spo11-DSB formation are skewed towards pericentromeric regions and regions that load pro-DSB factors early—revealing regions of preferential priming—but this effect is abolished when NDT80 is deleted. Our work highlights how the stochastic nature of Spo11-DSB formation in individual cells within the limited temporal window of meiotic prophase can cause localised DSB clustering—a phenomenon that is exacerbated in tel1∆ cells due to the dual roles that Tel1 has in DSB interference and meiotic prophase checkpoint control.

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ANKRD31 anchors meiotic double-strand break formation as a direct partner of REC114

Project description:Homologous recombination initiated by double-strand breaks (DSBs) is crucial for chromosome pairing and segregation during meiosis. Here we unveil mouse ANKRD31 as a lynchpin controlling DSB formation. Spermatocytes lacking ANKRD31 have altered DSB locations and fail to target DSBs to X and Y pseudoautosomal regions (PAR). They also have delayed and fewer recombination sites but, paradoxically, more total DSBs, indicating DSB dysregulation. Unrepaired DSBs and pairing failures—stochastic on autosomes, nearly absolute on X and Y—cause meiotic arrest and male sterility, while Ankrd31-deficient females have reduced oocyte reserves. A crystal structure defines direct ANKRD31–REC114 molecular contacts and reveals a surprising pleckstrin homology domain in REC114. In vivo, ANKRD31 recruits REC114 to the PAR and elsewhere. Our findings inform a model that ANKRD31 is a scaffold anchoring REC114 and other factors to specific genomic locations, promoting efficient and timely DSB formation but also suppressing formation of clustered DSBs.

2019-12-25 | GSE118913 | GEO

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