Restoring Shugoshin 1 reduces chromosome errors in human eggs

Abstract

Aneuploidy in human eggs, which rises sharply with age, is a leading cause of infertility, IVF failure, and miscarriage. This age-related aneuploidy is primarily driven by premature sister chromatid separation (PSSC), resulting from loss of the cohesin complex that holds chromatids together. How cohesin is destabilized in the long-lived mammalian oocyte is poorly understood. Here, we show that in mouse oocytes, pericentromeric transcription is essential for maintaining the cohesion protector Shugoshin 1 (SGO1) and PP2A at centromeres, which together safeguard the cohesin subunit REC8. With age, mouse oocytes lose pericentromeric transcription, SGO1, and PP2A, leading to destabilized cohesion and increased PSSC. Supplementing aged mouse oocytes with Sgo1 restores centromeric protection, and reduces PSSC to youthful levels. Aged human oocytes also show reduced SGO1, and SGO1 supplementation reduces the fraction of human eggs with PSSC by approximately half. These findings establish SGO1 supplementation as a potential strategy to preserve chromatid cohesion in aging oocytes.