Disordered protein COSA-2 maintains crossover-specific repair compartments to ensure meiotic crossover maturation

Introduction

The continuity of life depends on the faithful propagation of genetic material. In sexual organisms, this relies on meiotic recombination and crossover (CO) formation, which are crucial for accurate segregation of homologous chromosomes and the shuffling of parental alleles (Hunter, 2015).

The germline of the nematode Caenorhabditis elegans has been an excellent model for dissecting the molecular mechanism of meiotic recombination, as complete meiotic progression can be observed in a spatially and temporally organized sequence along the gonad arms. Recombination is initiated by the conserved topoisomerase-like enzyme Spo11/SPO-11 which creates excessive double-strand breaks, that are resected to generate 3’ overhanging strands loaded with RAD-51. This coincides with homolog pairing and synapsis, forming the synaptonemal complex (SC) between chromosome axes, during early meiotic prophase, essential for subsequent crossover (Hunter, 2015; Lui and Colaiácovo, 2013).

As meiosis progresses, all but one double-strand break per chromosome are resolved and repaired; the remaining break forms a double-Holliday junction and is designated as the crossover site. Crossover designation is reinforced by the cyclin-related protein CNTD1/COSA-1 in complex with the cyclin-dependent kinase CDK-2. Together, COSA-1-CDK-2 promotes the phosphorylation and local retention of RING-finger proteins ZHP-3/4 and the MutSγ/MSH-5 complex, which stabilizes the joint DNA molecules, at the crossover site (Haversat et al., 2022; Lui and Colaiácovo, 2013).

In this new preprint, the authors identified a novel component of the crossover machinery, named COSA-2 (crossover-site-associated-2). COSA-2 is an intrinsically disordered protein specifically required to maintain the assemblages of CO-promoting factors at sites of crossover maturation (Uebel et al., 2026). Failure of this process may lead to “crossover maturation inefficiency”, resulting in germ-cell aneuploidy and infertility, as observed in mammals.

Major findings

1) COSA-2 is required for crossover formation

Uebel and colleagues found that loss of cosa-2, a gene encoding an intrinsically disordered protein, caused profound defects in meiotic recombination, while upstream events – including double-strand break formation, homolog pairing, and synapsis – appeared to be unaffected. The mutants produced a high frequency of inviable embryos and univalents that lacked chiasmata, which normally connect homologous chromosome pairs in wild-type oocytes at late diakinesis.

By examining the endogenous expression of COSA-2, the authors found that it appeared suddenly as foci in germ cell nuclei at the late pachytene stage of meiotic prophase, colocalizing with COSA-1, BLM, MSH-5 at the crossover sites. The interaction between COSA-2 and COSA-1 was supported by both Alpha-Fold predictions and proximal labeling by TurboID.

2) COSA-2 functions as “molecular glue” that promotes crossover maturation

Notably, in cosa-2 mutants, COSA-1, BLM, and MSH-5 were detected as multiple foci in early pachytene nuclei, corresponding to early double-strand break repair intermediates, but failed to accumulate at crossover sites and become undetectable by late pachytene. In wild type, ZHP-3 was initially distributed along the length of the synaptonemal complex in early pachytene and subsequently co-concentrated with other crossover factors at crossover sites in late prophase; this redistribution was absent in germ cells lacking cosa-2.

Consistent with the notion that COSA-2 is specifically required for crossover maturation, the authors showed that six CO-designated intermediates – one per chromosome pair, marked by phosphorylated MSH-5 foci occasionally reflecting a dHJ conformation – were initially formed in cosa-2 mutants but failed to mature into crossovers.

Finally, using conditional depletion of COSA-2 with the auxin-inducible degron system, Uebel and team found that COSA-2 functioned specifically during the first half of late pachytene, termed the “COSA-2 execution point”. Loss of COSA-2 within this narrow window led to rapid disruption of CO factors’ localization and ultimately prevented chiasma formation.  However, loss of COSA-2 (and the subsequent dismantling of crossover factor assemblages) in the second half of late pachytene resulted in chiasma formation and the production of viable embryos, suggesting the critical processes of crossover formation had been completed by this point.

Together, these results strongly suggest that COSA-2 serves as a “molecular glue” that concentrates and maintains crossover factors, allowing CO intermediates to mature into completed crossovers.

Questions for the authors

1) Is COSA-2 phosphorylated by the COSA-1-CDK-2 complex?

2) What might be the signal that recruits COSA-2 during late pachytene?

2) What are the future directions that follow from this study?

Why I chose to highlight this preprint:

This preprint beautifully demonstrates the complex molecular machinery required to maintain the fidelity of meiotic recombination – a fundamental developmental process in all sexually-reproducing organisms. The authors have done an excellent job dissecting the functions of COSA-2 and alluding to a potentially conserved mechanism involving the human protein PRR19, which may have important implications for reproductive medicine.

References

Haversat, J., Woglar, A., Klatt, K., Akerib, C. C., Roberts, V., Chen, S.-Y., Arur, S., Villeneuve, A. M. and Kim, Y. (2022). Robust designation of meiotic crossover sites by CDK-2 through phosphorylation of the MutSγ complex. Proceedings of the National Academy of Sciences 119, e2117865119.

Hunter, N. (2015). Meiotic Recombination: The Essence of Heredity. Cold Spring Harb Perspect Biol 7, a016618.

Lui, D. Y. and Colaiácovo, M. P. (2013). Meiotic Development in Caenorhabditis elegans. Adv Exp Med Biol 757, 133–170.

Uebel, C. J., Deng, D. Y., Kim, Y. and Villeneuve, A. M. (2026). Disordered protein COSA-2 maintains crossover-specific repair compartments to ensure meiotic crossover maturation. 2026.05.13.725012.[preprint]

 

Tags: meiosis, nematode, reproduction

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