As females age, the frequency of aneuploid gamete formation increases, primarily due to errors in meiotic chromosome segregation, which can be influenced by various genetic and environmental factors (Liu and Gao, 2023). Notably, the age-related loss of sister chromatid cohesion is a key contributor to the rise in aneuploidy. Studies suggest that sister chromatid cohesion can only be established before or upon meiotic entry and maintained throughout the extended meiotic prophase. Impaired sister chromatid cohesion in the chromosomes of oocytes from aged females results in increased distances between kinetochores and a higher probability of aneuploidy (Chiang et al., 2011; Duncan et al., 2012).

Cohesin is a multi-subunit protein complex that is ubiquitous in eukaryotes and highly conserved from yeast to humans (Peters and Nishiyama, 2012). It consists of four core subunits: two structure maintenance of chromosome (SMC) subunits, SMC-1 and SMC-3 in Caenorhabditis elegans (C. elegans), an α-kleisin subunit (sister chromatid cohesion 1 [SCC-1] or its paralogs in C. elegans), and an stromal antigen (SA) subunit (SCC-3 in C. elegans). SMC-1 and SMC-3 fold through their hinge regions, each forming 50 nm-long antiparallel coiled coils (arms) that bring their N- and C-termini together, forming a composite globular ATPase head domain. Within the cohesin ring, the N-terminus of the kleisin subunit interacts with the SMC-3 neck, while the C-terminus interacts with the SMC-1 head. Additional regulatory proteins, such as PDS-5 and WAPL-1, can be recruited to the cohesin complexes to ensure their proper functions (Nasmyth and Haering, 2005; Haarhuis et al., 2014; Goto et al., 2017).

During meiosis, the meiosis-specific kleisin subunit REC-8 replaces the mitotic subunit SCC-1. In addition to REC-8, there are two additional meiosis-specific kleisin subunits in C. elegans, COH-3 and COH-4, which are highly identical and functionally redundant. These meiosis-specific subunits confer a unique and essential function to cohesin in meiosis, making it critical in forming sister chromatid cohesion (Nasmyth and Haering, 2005), maintaining the correct orientation and segregation of sister chromatids, promoting chromosome pairing and synapsis (Molnar et al., 1995; Klein et al., 1999), and mediating DNA double-strand break (DSB) formation and repair (Ellermeier and Smith, 2005; Fowler et al., 2013; Phadnis et al., 2015).

Previous studies have linked mutations in cohesin subunits to reproductive diseases, such as non-obstructive azoospermia or primary ovarian insufficiency caused by mutations in stromal antigen 3 (STAG3) (Akbari et al., 2022). Additionally, loss-of-function mutations in cohesin proteins are associated with various human diseases. For example, mutations in radiation sensitive 21 (RAD21), Nipped-B-like protein (NIPBL), or structural maintenance of chromosomes 1A (SMC1A) lead to Cornelia de Lange syndrome (Krab et al., 2020), mutations in establishment of cohesion 1 homolog 2 (ESCO2) cause Roberts syndrome (Schüle et al., 2005), mutations in STAG2, RAD21, SMC1A, or SMC3 are linked to acute myeloid leukemia (Eckardt et al., 2023), and mutations in RAD21 are associated with lymphoblastic leukemia (Schedel et al., 2022). However, it remains largely unclear how missense mutations within the cohesin subunits may affect meiotic chromosome segregation during aging.

Here, we assess the impact of several hypomorphic missense mutations located at different positions within SMC-1 on reproduction in C. elegans. We found that mutations outside the SMC-1 head domain did not affect meiosis or reproduction. In contrast, hydrophobic mutations within the SMC-1 head domain, which were biochemically tested not to affect SMC–kleisin interaction, impact the accuracy of meiotic chromosome segregation in worms. Interestingly, a severe mutation exhibited a surprisingly ameliorated phenotype with aging. This improvement is linked to a slowed meiotic progression during early prophase, which allows for the restoration of impaired cohesin loading. Our study links point mutations within the cohesin subunit to meiotic defects and reproductive aging, revealing how cohesin variants, meiotic progression speed, and duration shape the accuracy of meiotic chromosome segregation.