Meiotic cohesion requires Sirt1 and preserving its activity in aging oocytes reduces missegregation

Abstract

Chromosome segregation errors in human oocytes increase dramatically as women age and premature loss of meiotic cohesion is one factor that contributes to a higher incidence of segregation errors in older oocytes. Here we show that cohesion maintenance during meiotic prophase in Drosophila oocytes requires the NAD+-dependent deacetylase, Sirt1. Knockdown of Sirt1 during meiotic prophase causes premature loss of arm cohesion and chromosome segregation errors. We have previously demonstrated that when Drosophila oocytes arrest and age in diplotene, segregation errors increase significantly. By quantifying acetylation of the Sirt1 substrate H4K16 on oocytes chromosomes, we find that Sirt1 deacetylase activity declines markedly during aging. However, if females are fed the Sirt1 activator SRT1720 as their oocytes age, the H4K16ac signal on oocyte DNA remains low in aged oocytes, consistent with preservation of Sirt1 activity during aging. Strikingly, age-dependent segregation errors are significantly reduced if mothers are fed SRT1720 while their oocytes age. Our data suggest that maintaining Sirt1 activity in aging oocytes may provide a viable therapeutic strategy to decrease age-dependent segregation errors.