The effect of histone H3 and H4 mutants on the chronological lifespan of Saccharomyces cerevisiae

[摘要] In this study we maintained histone mutant strains in a batch culture. Weobserved that some strains significantly decreased at a lower rate in the quiescentpopulation.Some strains disappeared from quiescent population more rapidly,surprisingly, these strains did not increase in the non-quiescent population,suggesting that they may lyse and die.Residues that are implicated in lifespanextension are mostly histone tail residues and residues that are located in thesolvent accessible region, suggesting that these residues may be bound by anotherprotein(s) such as the silent information regulator, Sir3, via a BAH domain.Allresidues that are implicated in lifespan reduction are localised internally on thenucleosome core except for H3K18, suggesting their role in destabilising thenucleosome structure. This may allow elevated levels of DNA damage, and induceapoptosis.The gene expression studies of cells at late log phaseshowed that although allselected strains exhibited chronological lifespan extension, they had two distinctregulatory processes, suggesting that the H4K16Q and H4H18A strains, on the onehand, and the H3E50 strain on the other hand, may modulate different pathways toregulate chronological lifespan.The GO term enrichment for genes that aresignificantly up-regulated in the H4K16Q and H4H18A mutants, include rRNAprocessing and maturation, rRNA export, ribosome assembly, gene expression,cytoplasmic translation and ethanol metabolic processes. On the other hand, the GOterm enrichment for induced genes in H3E50A mutant, include, mitochondrialelectron transport, tricarboxylic acid cycle, ATP synthesis coupled proton transport,oxidative phosphorylation, glutamate metabolic process, glyoxylate cycle, and purine ribonucleoside triphosphate biosynthetic process. In addition, response to hydrogenperoxide, reactive oxygen species metabolic process, and response to oxidativestress appeared. It appears that many metabolic processes are upregulated in theH3E50A mutant strain. It is likely that the increased metabolism leads to storage ofenergy to be used in long starvation periods.The proteome studies of H4K16Q and H4H18A mutants at late stages ofgrowth showed similar profiles. Snz1 is involved in vitamin B6 biosynthesis. It isregulated by, among others, Rap1. Jhd2 induction is interesting because it is ahistone demethylase involved in global demethylation of H3K4, a histone markadded by Set1 and associated with active transcription. Gcy1 is a glyceroldehydrogenase, and was shown to increase in response to DNA replication stress.In H3E50A mutant, ribosomal protein, RPL16B, which is regulated by Rap1 wasupregulated. Scs2 is involved in phospholipid metabolism, it was also shown thatScs2 over-expression rescued telomeric shortening and was de-repressed in a strainover-expressing Mec1. Tfs1 is an inhibitor of carboxypeptidase Y, and was alsoshown to regulate the PKA signalling pathway.We propose that Sir3, which is recruited to the silent chromatin by Rap1,cannot bind to the telomere nucleosomes, therefore, Rap1 redistributes to otherregions of the genome of histone mutants. The regions, which Rap1 may relocate to,include stress response, DNA replication and damage stress response, and telomeremaintenance genes.

[发布机构] University of the Free State