PIKK division of labour in non-mammalian meiosis: local break control versus synapsis surveillance

Question: How do the PIKK kinases ATM, ATR and DNA-PK coordinate meiotic recombination and germ cell elimination in organisms other than mammals, such as Drosophila, C. elegans and yeast?

Answer

Across the retrieved papers, the non-mammalian evidence supports a two-arm model rather than a linear hierarchy: ATM/Tel1 operates at the level of the programmed break itself — recruited to meiotic DSB hotspots and axis sites, it suppresses nearby break formation and, through a partly separable output, holds meiotic prophase exit — while ATR/Mec1 operates at the interface between recombination and chromosome structure, phosphorylating synaptonemal complex components and feeding the checkpoint that decides whether a nucleus proceeds or is removed. Where the terminal elimination step has been resolved in invertebrates, it is executed by organism-specific machinery (yeast prophase I exit delay, C. elegans germline apoptosis, Drosophila spermatid elimination) whose coupling to a specific PIKK is usually inferred from damage-input experiments rather than from physiological recombination. DNA-PK is the conspicuous absentee: no retrieved non-mammalian germline study in this window assigns it a meiotic function, and its only mechanistic datum here places it upstream of ATR in Xenopus extracts, outside meiosis.

Tel1/ATM regulates where breaks are made, not only what happens after they are made

Tel1 is recruited to meiotic DSB hotspots and chromosomal axis sites in a DSB-dependent manner, consistent with breaks forming within the chromosome-axis environment predicted by the tethered loop-axis complex model [9]. Tel1 occupancy at breaks is not merely surveillance: it suppresses coincident DSB formation in neighbouring hotspots, the phenomenon of DSB interference [9]. Quantitative modelling of this local negative feedback shows that combining innate chromosome-specific DSB patterns with interference generates complex population-level redistribution of breaks, defines the spatial range over which interference propagates, and requires both Tel1 recruitment via Xrs2 and Tel1 kinase activity [10]. The same logic appears in a mammal: loss of ATM dysregulates DSB distribution and permits closely spaced double cuts that generate microdeletions and structural variants, with MRE11 and ATM proposed to cooperate in locally regulating DSB distributions [2].

Tel1's interference and checkpoint outputs are genetically separable

Recruitment of Tel1 to meiotic DSBs, DSB interference and the meiotic DNA damage checkpoint all depend on the C-terminal moiety of Xrs2 that mediates the Tel1–Xrs2 interaction [9]. Mutating the Xrs2 FxF/Y motif that stabilises Tel1–Xrs2 binding, however, leaves DSB interference intact while abolishing the Tel1-dependent DNA damage checkpoint, demonstrating that these two Tel1 functions are separable outputs of the same recruitment event [9]. On the modelling side, mutation of potential Rec114 phosphorylation sites indicates that Rec114 is not an essential target of Tel1 for interference, leaving the effector of the spatial output unidentified [10]. The checkpoint output, by contrast, has a defined downstream architecture: synapsis and recombination defects delay prophase I exit by inhibiting Ndt80-dependent expression of CLB1 and CDC5, with Swe1 essential for checkpoint maintenance but not for its initial activation [15].

ATR/Mec1 acts on the synapsis interface rather than solely as a break transducer

Heterologous (non-homologous) synapsis in budding yeast initiates along chromosome arms after DSB resection, carries canonical crossover-repair markers, but does not require recombinase-dependent strand invasion; instead it requires the DNA-damage sensor kinase ATR/Mec1, which phosphorylates a specific residue in Zip1, the major transverse filament protein of the synaptonemal complex [11]. Phospho-mimetic ZIP1 mutants rescue the synapsis defect of mec1 mutants and partially restore gamete viability, indicating that this structural, non-canonical Mec1 function — not merely damage signalling — is required for faithful meiotic completion [11]. Mec1 also acts upstream of the meiosis-specific Mek1 kinase: Mek1 activation is dictated by Red1-Hop1-Mek1 complex formation and upstream DNA-break-dependent signalling, and Mek1 can be activated in mitotic cells under DNA-damaging conditions in a Mec1-dependent manner [14]. In C. elegans, the analogous regulatory layer is phosphorylation of the BRC-1/BRD-1 heterodimer: blocking damage-induced phosphorylation causes meiotic DSB accumulation, chromosome breakage, catastrophic diakinesis and loss of fecundity, driven by Bloom and MUS-81 activity [4].

The elimination step is organism-specific and only loosely tied to a named PIKK

In C. elegans, germline apoptosis removes oocytes that contain DNA damage or multiple nuclei, and blocking apoptosis reduces fecundity, perturbs rachis morphology and yields small, low-viability oocytes and embryos [3]. The PIKK-to-apoptosis connection in the worm germline has been demonstrated for exogenous damage: sanguinarine-induced germ-cell apoptosis in the proliferative germline requires DNA-damage-induced p53/CEP-1 activity and ATM/ATR-mediated CHK-1 signalling, and is suppressed by ROS scavenging [7]. In Drosophila, the elimination machinery resolved in this window acts post-meiotically: gamma-irradiation specifically compromises spermatogenesis to eliminate damaged nuclei, and the histone variant H2Av has a non-canonical role in spermatid elimination, defining a haploid-specific genome quality-control program [6]. Earlier in the fly germline, loss of bru1 elevates Mei-W68 and produces ectopic, persistent DSBs and cell death that is potentially p53-mediated [13]. Checkpoint suppression, rather than activation, can also be the regulated step: in Bombyx mori apyrene spermatogenesis, meiotic genes and cell cycle checkpoint factors are downregulated, and Sex-lethal acts in checkpoint inactivation to allow this error-prone meiosis to proceed [1].

Conflicts and gaps

The identity of the meiotic surveillance kinase differs between systems in a way the retrieved papers do not reconcile. In budding yeast, DSB interference and the meiotic DNA damage checkpoint are Tel1/ATM functions [9], whereas in mouse oocytes meiotic surveillance is mediated by ATR, with ATR removal rescuing oocyte loss in response to asynapsis and to persistent meiotic DSBs, while ATM dominates only the response to postnatal irradiation with ATR and DNA-PK acting redundantly [8]. Whether this reflects a genuine inversion of wiring or merely different assays (break patterning versus germ-cell elimination) is untested. The physiological trigger for C. elegans PIKK signalling is unresolved: the ATM/ATR–CHK-1–CEP-1 axis was defined with a xenobiotic ROS generator [7], and the kinase responsible for damage-induced BRC-1/BRD-1 phosphorylation is not identified in that study's findings [4]. Drosophila is the largest gap: no retrieved paper assigns tefu/ATM, mei-41/ATR or DNA-PKcs a function in meiotic recombination or germ-cell elimination, and the apoptotic events described are attributed to p53 or to H2Av rather than to an apical PIKK [13] [6]. Notably, germline apoptosis is not required for the male-versus-hermaphrodite difference in crossover control in C. elegans, so not every germline phenotype that looks checkpoint-like is apoptosis-linked [5].

What would change the answer

Stage-specific, conditional degradation of tefu, mei-41 and DNA-PKcs in Drosophila germ cells, scored against Mei-W68-dependent DSB formation, γH2Av, crossover-designation markers and spermatid elimination, would establish whether the insect germline uses a mouse-like ATR-centric surveillance axis or a yeast-like Tel1-centric break-patterning axis. In C. elegans, an ATL-1/ATM-1 degron combined with timed SPO-11 inactivation and CEP-1-dependent apoptosis readouts would separate programmed-break surveillance from exogenous-damage signalling, while mapping the BRC-1/BRD-1 phosphosites onto candidate PIKK consensus motifs would name the missing kinase. In yeast, separation-of-function Tel1 alleles coupled to quantitative DSB mapping (Spo11-oligo sequencing) and axis-recruitment assays are needed to identify the effector of interference, since Rec114 appears not to be it [10]. Finally, the DNA-PK arm requires a system in which the kinase exists and meiosis is tractable: the demonstration that DNA-PKcs phosphorylates TOPBP1 at S1131 in parallel to ATM to drive ATR signalling in Xenopus egg extracts provides the mechanistic template for asking whether an analogous DNA-PKcs–ATR relay operates in non-mammalian oocytes [12].

References

[1] Benner, L., Richmond, M., Xiang, Y., Lee, L., Li, T., Yu, Z., Tsuchiya, D., Huang, S., Hockens, C. B., Tromer, E. C., Hawley, R. S., Rosin, L. F.. "Programmed meiotic errors facilitate dichotomous sperm production in the silkworm, Bombyx mori". bioRxiv. 2025-09-02T00:00:00.000Z. URL: https://doi.org/10.1101/2025.08.03.667510

[2] Lukaszewicz, A., Wilson, T. E., Kim, S., Keeney, S., Jasin, M.. "MRE11 suppresses germline mutagenesis at meiotic double-strand breaks in mice". bioRxiv. 2026-02-15T00:00:00.000Z. URL: https://doi.org/10.64898/2026.02.11.705388

[3] Saydee-Onwubiko, U. N., Werner, M. E., Trapp, G. C., Maddox, A. S.. "Apoptosis promotes fertility in C. elegans by maintaining functional germline morphology". bioRxiv. 2025-12-11T00:00:00.000Z. URL: https://doi.org/10.1101/2025.10.22.683972

[4] Fernandez-Fernandez, N., Chacon, M., Camino, L. P., Garcia-Muse, T.. "Damage-induced phosphorylation of BRC-1/BRD-1 in meiosis preserves germline integrity". bioRxiv. 2025-03-31T00:00:00.000Z. URL: https://doi.org/10.1101/2025.03.30.646171

[5] Engebrecht, J., Calidas, A., Li, Q., Ruiz, A., Padture, P., Barroso, C., Martinez-Perez, E., Silva, N.. "Loss of meiotic double strand breaks triggers recruitment of recombination-independent pro-crossover factors in C. elegans spermatogenesis". bioRxiv. 2025-06-13T00:00:00.000Z. URL: https://doi.org/10.1101/2025.06.10.658785

[6] Kitaoka, M., Yamashita, Y. M.. "A genome quality control program for the haploid stage of spermatogenesis". bioRxiv. 2026-07-28T00:00:00.000Z. URL: https://doi.org/10.64898/2026.07.27.740997

[7] El Ghali, R., Izadi, M., Alrayyes, Z., Ali, T. A., Uddin, S., Pourkarimi, E.. "Sanguinarine activates ATM/ATR-mediated CHK-1 signaling to drive p53-dependent apoptosis in the C. elegans germline". bioRxiv. 2026-01-27T00:00:00.000Z. URL: https://doi.org/10.64898/2026.01.26.701699

[8] Sioutas, G., Perry, M. J., Zielinska, A. P., Elinati, E., Fallesen, T., Dao, V., Ojarikre, O., Turner, J.. "Stage-specific checkpoint signalling by ATM, ATR and DNA-PK safeguards oocyte genome integrity". bioRxiv. 2026-10-19T00:00:00.000Z. URL: https://doi.org/10.64898/2026.10.13.758765

[9] Dorme, M., Luciano, P., Cayrou, C., Aithal, R., Vernerey, J., Borde, V., Geli, V., llorente, b., Garcia, V. C.. "Xrs2 C-terminus mediates Tel1-dependent meiotic double-strand break interference". bioRxiv. 2025-08-25T00:00:00.000Z. URL: https://doi.org/10.1101/2023.10.17.561996

[10] Neale, M. J., Lopez Ruiz, L. M., Harper, J. A., Johnson, D., Allison, R. M., Gittens, W. H., Brown, G. G., Cooper, T. J., Garcia, V. C.. "Localised negative feedback shapes genome-wide patterning of meiotic DNA breaks". bioRxiv. 2026-02-24T00:00:00.000Z. URL: https://doi.org/10.64898/2026.02.23.706156

[11] Lotka, L. M., MacQueen, A. J., Milano, C. R., Hollingsworth, N. M., Hochwagen, A.. "Two distinct modes of meiotic chromosome synapsis". bioRxiv. 2026-08-23T00:00:00.000Z. URL: https://doi.org/10.64898/2026.08.19.745786

[12] Huynh, O., Michael, W.. "An NHEJ-independent Role for DNA-PKcs in ATR activation at DNA Double-Strand Breaks". bioRxiv. 2026-06-22T00:00:00.000Z. URL: https://doi.org/10.64898/2026.06.19.733426

[13] GARRIDO-MARAVER, J., Estella, C., Gonzalez-Reyes, A.. "Genetic control of mitotic-to-meiotic transition regulates germline cell survival". bioRxiv. 2026-06-01T00:00:00.000Z. URL: https://doi.org/10.64898/2026.05.28.728457

[14] Chen, L., Nivsarkar, V. N., Funk, S. K., Weir, J. R., Vader, G.. "Organizational principles governing assembly and activation of the meiosis-specific Red1-Hop1-Mek1 complex". bioRxiv. 2025-08-01T00:00:00.000Z. URL: https://doi.org/10.1101/2022.04.06.487319

[15] Gonzalez-Arranz, S., Acosta, I., Gil-Torres, I., Queralt, E., Santos, B., San-Segundo, P. A.. "Polo-like kinase Cdc5 orchestrates Cdk1 regulation via Swe1 and Mih1 during meiotic prophase I exit". bioRxiv. 2025-12-25T00:00:00.000Z. URL: https://doi.org/10.64898/2025.12.23.696139

How this survey was made

This survey answers one question: “How do PIKK kinases ATM, ATR and DNA-PK coordinate meiotic recombination and germ cell elimination in organisms other than mammals, such as Drosophila, C. elegans and yeast?”

We keep our own collection of recent preprints and refresh it every day from bioRxiv, medRxiv, arXiv, PsyArXiv, SocArXiv and ChemRxiv. For each survey, we search that collection for recent work and keep the strongest matches: papers that use the same terms as the question, and papers on the same topic in different words.

The text was written from the titles and abstracts of those papers; the full texts were not read. Statements that draw on a particular paper are marked with a number in brackets. The reference list just above is the 15 papers whose work this text draws on, chosen from the 123 papers those searches returned; the rest of the shortlist is not printed. It is not a complete review of everything published on the question.

Treat this as a starting point and a reading list, not a peer-reviewed review. The searches behind this survey ran on October 22, 2026 and covered work from the previous two years.