Messenger RNA 생성 및 분해에 의한 세포 수명 조절

Abstract

Several important cellular aging processes have been identified in the regulation of yeast replicative life span, including the accumulation of extrachromosomal rDNA circles (ERCs), transcriptional silencing at the rDNA mediated by the Sir2 and Rpd3 histone deacetylases, genomic instability, mitochondrial signaling to the nucleus, and oxidative stress. Numerous studies have examined the role of these processes in yeast aging. However, it is unclear how aberrant mRNA transcripts produced by THO/TREX mutants in the nucleus are caused cellular aging in yeast. First, we found that deletion of THO complex components, hpr1? and tho2?, and TREX2 complex components, thp1?, sac3? and sus1?, showed short lived. These short lived mRNA export factor and Sir2 are functioning in nonidentical pathways to promote longevity. Our results indicate that aberrant mRNA transcripts, not snoRNAs, produced by hpr1? and tho2? in the nucleus mainly caused short lived replicative lifespan in yeast. Second, we show that Rrp6 plays a role in genome-wide mRNA degradation. We performed genome-wide microarray analyses in hpr1?, rrp6? and hpr1?rrp6? strains. Our results show that most of genes which repressed in hpr1? and derepressed in hpr1?rrp6?. Comparing hpr1? and hpr1?rrp6? mutants, 97.4% of all genes had mRNA levels restored relative to wild-type. Our Genome-wide microarray expression profiles showed almost identical patterns, an epistatic effect was observed in hpr1?rrp6?. Third, we applied artificially expressed bacterial Rho termination factor in yeast cells that the bacterial Rho expression shows mimicking hpr1? state at least replicative lifespan regulation in yeast. Thus, our findings imply that Rho action leads to the production of full length yet defective mRNPs that causes decrease in cellular lifespan in yeast. Also, Rho-induced defective mRNPs will be recognized as export-incompetent and eliminated by the exosome-mediated nuclear quality control system. Taken together, our data reveal that aberrant mRNA transcripts produced by THO/TREX mutants in the nucleus caused cellular aging in yeast. Our results strongly suggest that nuclear surveillance systems regulate cellular lifespan at least in yeast via a pathway that is not shared with other known mechanisms for lifespan pathway.