The effect of histone H3 and H4 mutants on the chronological lifespan of Saccharomyces cerevisiae
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Date
2015
Authors
Ngubo, Mzwanele
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Publisher
University of the Free State
Abstract
In this study we maintained histone mutant strains in a batch culture. We
observed that some strains significantly decreased at a lower rate in the quiescent
population.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 lifespan
extension are mostly histone tail residues and residues that are located in the
solvent accessible region, suggesting that these residues may be bound by another
protein(s) such as the silent information regulator, Sir3, via a BAH domain.All
residues that are implicated in lifespan reduction are localised internally on the
nucleosome core except for H3K18, suggesting their role in destabilising the
nucleosome structure. This may allow elevated levels of DNA damage, and induce
apoptosis.
The gene expression studies of cells at late log phaseshowed that although all
selected strains exhibited chronological lifespan extension, they had two distinct
regulatory processes, suggesting that the H4K16Q and H4H18A strains, on the one
hand, and the H3E50 strain on the other hand, may modulate different pathways to
regulate chronological lifespan.The GO term enrichment for genes that are
significantly up-regulated in the H4K16Q and H4H18A mutants, include rRNA
processing and maturation, rRNA export, ribosome assembly, gene expression,
cytoplasmic translation and ethanol metabolic processes. On the other hand, the GO
term enrichment for induced genes in H3E50A mutant, include, mitochondrial
electron 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 hydrogen
peroxide, reactive oxygen species metabolic process, and response to oxidative
stress appeared. It appears that many metabolic processes are upregulated in the
H3E50A mutant strain. It is likely that the increased metabolism leads to storage of
energy to be used in long starvation periods.
The proteome studies of H4K16Q and H4H18A mutants at late stages of
growth showed similar profiles. Snz1 is involved in vitamin B6 biosynthesis. It is
regulated by, among others, Rap1. Jhd2 induction is interesting because it is a
histone demethylase involved in global demethylation of H3K4, a histone mark
added by Set1 and associated with active transcription. Gcy1 is a glycerol
dehydrogenase, and was shown to increase in response to DNA replication stress.
In H3E50A mutant, ribosomal protein, RPL16B, which is regulated by Rap1 was
upregulated. Scs2 is involved in phospholipid metabolism, it was also shown that
Scs2 over-expression rescued telomeric shortening and was de-repressed in a strain
over-expressing Mec1. Tfs1 is an inhibitor of carboxypeptidase Y, and was also
shown 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 other
regions of the genome of histone mutants. The regions, which Rap1 may relocate to,
include stress response, DNA replication and damage stress response, and telomere
maintenance genes.
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Keywords
Saccharomyces cerevisiae, Histone mutants, Longevity, Chronological lifespan, Cellular stress response, Chromatin, Epigenetics, Aging, Thesis (Ph.D. (Biotechnology))--University of the Free State, 2015