Abstract
Production of healthy gametes in meiosis relies on the quality control and proper distribution of both nuclear and cytoplasmic contents. Meiotic differentiation naturally eliminates age-induced cellular damage by an unknown mechanism. Using time-lapse fluorescence microscopy in budding yeast, we found that nuclear senescence factors - including protein aggregates, extrachromosomal ribosomal DNA circles, and abnormal nucleolar material - are sequestered away from chromosomes during meiosis II and subsequently eliminated. A similar sequestration and elimination process occurs for the core subunits of the nuclear pore complex in both young and aged cells. Nuclear envelope remodeling drives the formation of a membranous compartment containing the sequestered material. Importantly, de novo generation of plasma membrane is required for the sequestration event, preventing the inheritance of long-lived nucleoporins and senescence factors into the newly formed gametes. Our study uncovers a new mechanism of nuclear quality control and provides insight into its function in meiotic cellular rejuvenation.
Highlights
Aging occurs as an organism loses its ability to maintain homeostasis over time
Senescence factors are sequestered away from chromosomes in meiosis II and subsequently eliminated To gain a deeper understanding of gametogenesis-induced rejuvenation, we first sought to characterize the meiotic dynamics of age-induced protein aggregates, ribosomal DNA (rDNA) circles, and other nucleolar damage using time-lapse fluorescence microscopy
In an aged precursor cell, many of its nuclear contents, including nuclear pore complexes, rDNA circles, nucleolar proteins and protein aggregates, are sequestered in a membranous compartment away from the chromosomes that are destined for future gametes (Figure 10)
Summary
Aging occurs as an organism loses its ability to maintain homeostasis over time. The cellular changes that accompany aging have been most extensively characterized in the budding yeast, Saccharomyces cerevisiae (Figure 1A; Denoth-Lippuner et al, 2014; Kaeberlein, 2010; Longo et al, 2012). Disrupted protein homeostasis results in the accumulation of carbonylated proteins and protein aggregates that contain oxidatively damaged proteins (Aguilaniu et al, 2003; Erjavec et al, 2007). The nucleus undergoes a number of changes including enlargement of the nucleolus (Lewinska et al, 2014; Morlot et al, 2018; Sinclair et al, 1997), misorganization of nuclear pore complexes (Lord et al, 2015), and accumulation of extrachromosomal ribosomal DNA (rDNA) circles (Denoth-Lippuner et al, 2014; Sinclair and Guarente, 1997). Many of the cellular changes that accrue with age are conserved across eukaryotes (Colacurcio and Nixon, 2016; David et al, 2010; Sun et al, 2016; Tiku et al, 2017)
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