Meiotic Cellular Rejuvenation is Coupled to Nuclear Remodeling in Budding Yeast

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 factorsincluding 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 old 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. 420 540 300 MergePM Nsr1 King and Goodman et al. Figure 6 -Supplement 3 PM initiation

The ESCRT-III complex is required for nuclear pore complex sequestration and regulates gamete replicative lifespan in budding yeast meiosis

“…To confirm that nucleoporin aggregation is not limited to certain NPC subcomplexes, we analyzed Pom34-GFP and Nup49-mApple together and observed their colocalization throughout meiosis, resulting in a change in positioning from along the nuclear periphery to the GUNC compartment Figure 1c . We also observed the aggregation of nucleoporins Nup170 and Pom152, as shown previously [ 31 ]. We therefore conclude that nucleoporins, including Nup49, Nup170, Pom34 and Pom152, are sequestered to GUNC and are largely excluded from the developing nuclei after anaphase II.…”

“…By live-cell fluorescence microscopy, we found similarly that Pom34, a subunit of the transmembrane ring of the NPC [ 39 ], aggregated like Nup49 Figures 1b and 1c . Our findings therefore confirm that nucleoporins are sequestered during meiosis II, leading to the formation of the fifth nuclear component [ 30 , 31 ], which is also called GUNC for gametogenesis uninherited nuclear compartment [ 40 ].…”

“…In addition, we observed an even distribution of INM-localized Heh1 throughout the nuclear periphery and the GUNC (Supplemental Figure 2 and [ 31 ]. Taken together, our findings indicate that nucleoporins, but not any NE-associated proteins, are selectively sequestered to the GUNC compartment.…”

Sex, senescence, sources and sinks

“…Importantly, despite A-age referring to the soma, an organism cannot always be expected to be at A-age zero when the zygote is freshly formed. For example, gametes in yeast are rejuvenated in a process where nuclear senescence factors and nucleoporins are sequestered away from chromosomes during meiosis II (King et al, 2019). Each set of simultaneously formed four gametes comes with one membrane-bound 'rubbish bin', which is subsequently destroyed.…”

“…But is it actually true that sex rejuvenates? Because sex often associates with germline segregation early in development and the repair of DNA double-strand breaks via recombination, it seems a priori more efficient than asexual modes of reproduction at producing offspring from cells with little accumulated damage and deleterious mutations (Mirzaghaderi & Hörandl, 2016, King et al, 2019, Box 2, but see Tan et al, 2012, Wang et al, 2019. But even in organisms with a segregated germline, gametes do not come from a lineage that was cryogenically frozen in an immaculate state.…”