Regulation of cellular lifespan by SAGA complex

Abstract

Over the last decade, great advances have been made in the study of how DNA-related cellular processes occur in the native chromatin environment. The yeast Spt-Add-Gcn5 Acytyl transferase (SAGA) transcriptional co-activator complex is known to regulate several cellular processes through coordination of histone post-transcriptional modifications, including acetylation, deubiquitination, and chromatin recognition. Although a previous report shows that the SAGA histone deubiquitinase (DUB) module controls lifespan via Sir2 interaction, less is known about the involvement of other SAGA modules in regulating lifespan. In the present study, I tried to determine the role of the SAGA modules, including the HAT (histone acetyltransferase) module, the SPT (Suppressor of Ty insertion) module, and SAGA ‘other’ module, in the regulation of two different yeast cellular ageing mechanisms, replicative lifespan (RLS) and chronological lifespan (CLS). I found that the deletion of the subunit in the HAT module or The SPT module generally reduced the RLS and CLS. Especially, loss of Ada2 in the HAT module,and Spt7 and Spt20 in the SPT module consistently reduce the lifespan significantly in both lifespan analyses. Loss of Chd1 leads to no significant change in RLS but decreased CLS, suggesting that Chd1 plays a more important role in the non-diving phase during the cell cycle. Unequal sister chromatid exchange assays further show that loss of the HAT module mostly increased the stability in the rDNA locus, whereas that of SPT module significantly decreased the stability, suggesting that lifespan regulation by SPT module involves maintenance of the genome stability in the rDNA locus. Moreover, I found that the SPT module, but not the HAT module, significantly affects the recombination frequency in the plasmid-based recombination assay. Notably, the deletion of Spt20 and Ada1 increases the homologous recombination between the two direct-repeats of LEU2 genes, while the loss of Spt7 unexpectedly reduced the frequency. Taken together, these results demonstrate that the modules of SAGA HAT, SPT and Chd1 have role in cellular lifespan regulation and suggest that genome stability at either rDNA loci or actively transcribed regions of genes is important for SPT module-mediated regulation of lifespan.