Human Oocytes Harbouring Damaged DNA Can Complete Meiosis-I

Abstract

Chromosomal abnormalities such as aneuploidies and DNA damage are considered a major threat to the establishment of healthy eggs and embryos. Recent landmark studies showed that mouse oocytes with damaged DNA can resume meiosis and undergo Germinal Vesicle Breakdown (GVBD), but then arrest in metaphase of meiosis-I in a process involving Spindle Assembly Checkpoint (SAC) signalling. Such a mechanism could help prevent the generation of metaphase-II (Met-II) eggs with damaged DNA. However we report that this is not the case in the human oocyte. DNA damage prevents human oocytes from undergoing GVBD in some cases. Strikingly however, most oocytes harbouring DNA damage progress through meiosis-I and subsequently extrude the first polar body (PB1) to form a metaphase-II egg, revealing the absence of a DNA-damage-induced SAC response. Analysis of the resulting metaphase-II eggs revealed highly disorganised spindles with misaligned and heavily damaged chromosomes. Our results suggest that DNA damage accumulated in meiosis-I, such as could occur during in vitro maturation procedures, does not prevent polar body extrusion and therefore could persist in morphologically normal looking metaphase-II eggs.