Unique geometry of sister kinetochores in human oocytes during meiosis I may explain maternal age-associated increases in chromosomal abnormalities

Abstract

The first meiotic division in human oocytes is highly error-prone and contributes to the uniquely high incidence of aneuploidy observed in human pregnancies. A successful meiosis I (MI) division entails separation of homologous chromosome pairs and co-segregation of sister chromatids. For this to happen, sister kinetochores must form attachments to spindle kinetochore-fibres emanating from the same pole. In mouse and budding yeast, sister kinetochores remain closely associated with each other during MI, enabling them to act as a single unified structure. However, whether this arrangement also applies in human meiosis I oocytes was unclear. In this study, we perform highresolution imaging of over 1900 kinetochores in human oocytes, to examine the geometry and architecture of the human meiotic kinetochore. We reveal that sister kinetochores in MI are not physically fused, and instead individual kinetochores within a pair are capable of forming independent attachments to spindle k-fibres. Notably, with increasing female age, the separation between kinetochores increases, suggesting a degradation of centromeric cohesion and/or changes in kinetochore architecture. Our data suggest that the differential arrangement of sister kinetochores and dual k-fibre attachments may explain the high proportion of unstable attachments that form in MI and thus indicate why human oocytes are prone to aneuploidy, particularly with increasing maternal age.

The proteomic landscape of centromeric chromatin reveals an essential role for the Ctf19CCANcomplex in meiotic kinetochore assembly

“…We propose that such kinetochore plasticity is necessary to perform distinct functions at different stages of meiosis. Loss of kinetochore integrity may contribute to age-related decline in female fertility, where gametogenesis is protracted (Patel et al, 2015;Zielinska et al, 2015Zielinska et al, , 2019. Our comprehensive analysis of meiotic kinetochore composition provides an extensive resource for the discovery of mechanisms underlying the specialised functions of kinetochores throughout meiosis.…”

“…Kinetochores play multiple roles in these meiosis-specific processes throughout the meiotic divisions (Brar and Amon, 2009). Importantly, kinetochore defects have been implicated in age-related oocyte deterioration in humans (Patel et al, 2015;Zielinska et al, 2015, 2019) and proposed to contribute to the high degree of meiotic chromosome segregation errors, causing infertility, birth defects and miscarriages Hassold and Hunt, 2001).…”

Meiosis: SUMO Keeps a Tight Grip on Sister Chromatids

“…Going forward, it will also be exciting to understand how the mitoCPR integrates or interacts with the other mitochondrial stress response pathways triggered by impaired mitochondrial protein import. At least two additional pathways are intimately linked to mitochondrial protein import, including mitophagy mediated by the kinase Pink1 and the UPR mt , which is regulated by the transcription factor ATFS-1 in worms and ATF4 and ATF5 in mammals [13,14]. Pink1, ATFS-1 and ATF5 are negatively regulated by mitochondrial protein import.…”

“…It will therefore be interesting to determine whether a deficit of the PIAS1-SUMO pathway at kinetochores is implicated in age-related premature separation of chromatids. Additionally, it will be important to determine whether similar mechanisms of protecting the centromeric cohesion between sister chromatids are in play in human oocytes, where sister kinetochores are more separated, even in oocytes from younger women [13,14].…”

The Effect of Dietary Folic Acid Supplementation on Female Germ Cell Aneuploidy

“…Observations in human oocytes reported a difference in iKT distance between young and old women up to 25.5% (Duncan et al, 2012;Patel et al, 2015). In addition, the fraction of split kinetochores was increased with advanced maternal age.…”