Maternal Smc3 protects the integrity of the zygotic genome through DNA replication and mitosis

Abstract

Aneuploidy is frequently observed in oocytes and early embryos, begging the question of how genome integrity is monitored and preserved during this critical period. SMC3 is a subunit of the cohesin complex that supports genome integrity, but its role in maintaining the genome in this window of mammalian development is unknown. We discovered that although depletion of Smc3 following meiotic S phase in mouse oocytes allowed accurate meiotic chromosome segregation, adult females were infertile. We provide evidence that DNA lesions accumulated following S phase in SMC3-deficient zygotes, followed by mitosis with lagging chromosomes, elongated spindles, micronuclei, and arrest at the 2-cell stage. Remarkably, although centromeric cohesion was defective, the dosage of SMC3 was sufficient to enable embryogenesis in juvenile mutant females. Our findings suggest that despite previous reports of aneuploidy in early embryos, chromosome missegregation in zygotes halts embryogenesis at the 2-cell stage. Smc3 is a maternal gene with essential functions in repair of spontaneous damage associated with DNA replication and subsequent chromosome segregation in zygotes, making cohesin a key protector of the zygotic genome.

Heterozygous loss-of-functionSMC3variants are associated with variable and incompletely penetrant growth and developmental features

“…Thus, we sought to further characterize LoF constraint in SMC3. Consistent with in vitro 38,39 and model organism studies 9,10,40,41 indicating SMC3 is an essential developmental gene, biallelic pLoF variants have never been described in a human being, including our cases.…”

“…In mice, sufficient SMC3 protein is required in oocytes for early embryonic development, 10 and heterozygous depletion of SMC3 in female mice has deleterious impacts on both the integrity and transmission of zygotic chromosomes. 9,10,12 Furthermore, conditional knockout of HDAC8 , an SMC3 recycling factor, causes subfertility. 57 Finally, several cohesin or cohesin-related genes have been implicated in infertility in humans ( REC8 , SMC1B , STAG3 , SGO2 ).…”

Cohesin is required for meiotic spindle assembly independent of its role in cohesion in C. elegans

“…Similar to C. elegans spo-11 rec-8 mutants, Drosophila sunn mutants lack SCC but retain non-cohesive c(2)m/SA cohesin (at least in pachytene) and form bipolar metaphase I spindles (Gyuricza et al, 2016). Depletion of SMC3, which should remove all cohesin from chromatin, has been reported in mouse oocytes (Yueh, Singh, & Gerton, 2021) and Drosophila oocytes (Gyuricza et al, 2016). Metaphase I spindle defects were not reported in either case.…”

Cohesin is required for meiotic spindle assembly independent of its role in cohesion in C. elegans

“…Depletion of SMC3, which should remove all cohesin from chromatin, has been reported in mouse oocytes [ 67 ] and Drosophila oocytes [ 68 ]. Metaphase I spindle defects were not reported in either case.…”