Oral Presentation ESA-SRB-APEG-NZSE 2022

Age-dependent loss of cohesin protection in human eggs (#256)

Bettina P Mihalas 1 , Gerard H Pieper 1 , Cerys E Currie 2 , David A Kelly 1 , Geraldine M Hartshorne 2 3 , Andrew D McAinsh 2 , Richard A Anderson 4 , Adèle L Marston 1
  1. Wellcome Centre for Cell Biology, University of Edinburgh, Edinburgh, Scotland, United Kingdom
  2. Centre for Mechanochemical Cell Biology & Division of Biomedical Sciences, University of Warwick, Coventry, England, United Kingdom
  3. University Hospitals Coventry and Warwickshire , University of Warwick, Coventry, England, United Kingdom
  4. Medical Research Council Human Reproductive Sciences Unit, University of Edinburgh, Edinburgh, Scotland, United Kingdom

Aneuploidy in human eggs is a major cause of miscarriage, infertility and birth defects. While it is prevalent throughout the female reproductive lifespan, aneuploidies associated with loss of cohesion between sister chromatids are greatly increased as women age. Loss of sister chromatid cohesion is largely attributed to an age-dependent loss of the cohesin ring complex. However, the molecular causes of cohesin loss are largely unknown. By using super-resolution microscopy, we demonstrate that a localisation-specific loss of the cohesin protector protein, Shugoshin 2 (SGO2), contributes to an increase in aneuploidy that is associated with cohesion loss in eggs from older women. We show that SGO2 localises in two pools in human eggs; (1) surrounding the kinetochore (centromere) and (2) across the chromatid junction (pericentromere bridge). We observed that SGO2 is progressively diminished from the pericentromere bridge in eggs from older women. The loss of this specific pool of SGO2 is accompanied by an increase in inter-kinetochore distance and the number of single chromatids suggesting reduced sister chromatid cohesion. In contrast, SGO2 association with kinetochores is independent of age, inter-kinetochore distance or the incidence of single chromatids. Further, we show that SGO2 at the pericentromere bridge coincides with a pool of cohesin in human eggs. We demonstrate that the localisation of SGO2 to the pericentromere bridge is dependent on MPS1 and BUB1 kinase activity. Notably, depletion of SGO2 by MPS1 inhibition in human oocytes during meiosis I results in loss of cohesin protection leading to an increase in single chromatids at meiosis II. Overall, our data suggest that the age-dependent loss of SGO2 at the pericentromere bridge in human eggs contributes to the loss of cohesion integrity and the increased incidence of aneuploidy observed in human eggs with age.