Impaired tRNA nuclear export links DNA damage and cell-cycle checkpoint.
In response to genotoxic stress, cells evoke a plethora of physiological responses collectively aimed at enhancing viability and maintaining the integrity of the genome. Here, we report that unspliced tRNA rapidly accumulates in the nuclei of yeast Saccharomyces cerevisiae after DNA damage. This response requires an intact MEC1- and RAD53-dependent signaling pathway that impedes the nuclear export of intron-containing tRNA via differential relocalization of the karyopherin Los1 to the cytoplasm. The accumulation of unspliced tRNA in the nucleus signals the activation of Gcn4 transcription factor, which, in turn, contributes to cell-cycle arrest in G1 in part by delaying accumulation of the cyclin Cln2. The regulated nucleocytoplasmic tRNA trafficking thus constitutes an integral physiological adaptation to DNA damage. These data further illustrate how signal-mediated crosstalk between distinct functional modules, namely, tRNA nucleocytoplasmic trafficking, protein synthesis, and checkpoint execution, allows for functional coupling of tRNA biogenesis and cell-cycle progression.
Ontario Cancer Institute, Division of Signaling Biology, Toronto, Ontario M5G-1L7, Canada. aghavide@uhnres.utoronto.ca
Ata
A
Ghavidel
Thomas
T
Kislinger
Oxana
O
Pogoutse
Richelle
R
Sopko
Igor
I
Jurisica
Andrew
A
Emili
D021581:Active Transport, Cell Nucleus / Q000502:physiology*; D017398:Alternative Splicing / Q000502:physiology; D050976:Basic-Leucine Zipper Transcription Factors; D002453:Cell Cycle / Q000235:genetics / Q000502:physiology*; D018797:Cell Cycle Proteins / Q000235:genetics; D002470:Cell Survival / Q000235:genetics; D064447:Checkpoint Kinase 2; D016213:Cyclins / Q000378:metabolism; D004249:DNA Damage / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000378:metabolism; D015536:Down-Regulation; D017353:Gene Deletion; D018816:Genes, cdc; D008954:Models, Biological; D028861:Nuclear Pore Complex Proteins / Q000235:genetics; D030781:Organisms, Genetically Modified; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D012343:RNA, Transfer / Q000378:metabolism*; D012441:Saccharomyces cerevisiae / Q000235:genetics*; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D014157:Transcription Factors / Q000378:metabolism
D050976:Basic-Leucine Zipper Transcription Factors; C082721:CLN2 protein, S cerevisiae; D018797:Cell Cycle Proteins; D016213:Cyclins; D004268:DNA-Binding Proteins; C501391:GCN4 protein, S cerevisiae; C408090:Los1 protein, S cerevisiae; D028861:Nuclear Pore Complex Proteins; D029701:Saccharomyces cerevisiae Proteins; D014157:Transcription Factors; D012343:RNA, Transfer; D064447:Checkpoint Kinase 2; D017346:Protein Serine-Threonine Kinases; C067022:RAD53 protein, S cerevisiae