Previously uncharacterized amino acid residues in histone H3 and H4 mutants with roles in DNA damage repair response and cellular aging.
FEBS J. 2018 Dec 07;:
Authors: Thakre PK, Sv A, Golla U, Chauhan S, Tomar RS
Abstract
Chromatin regulates gene expression and genome maintenance, and consists of histones and other components. The post translational modification of histones plays a key role in maintaining the structure and function of chromatin under different pathophysiological stress conditions. Here, we investigate the functions of previously unexplored amino acid residues in histones H3 and H4. To do so, we screened a library of yeast histone mutants following DNA damage and identified that substitution mutations of histone H3 (H3Q5A/E and H3Q120A) and H4 (H4Y88A/E and H4R78K) render yeast cells sensitive to DNA-damaging agents. These histone mutants show an activated DNA damage response, Rad53 phosphorylation and Sml1 degradation in the presence of MMS. In histone H3Q5A/E mutants, RNR2 and RNR3 genes were induced at low level, as was RNR3 in H4 histone mutants following DNA damage. In H3 mutant cells, the cell cycle was deregulated, leading to inefficient cell cycle arrest in the presence of MMS and genes involved in aging and DNA damage repair pathways were constitutively upregulated. In H3 mutants (H3Q5A, H3Q5E, and H3Q120A), we observed reduced chronological lifespan (CLS), compared to extended CLS in the H4R78K mutant. Histone mutants also showed altered H3K4me and H3K56ac modifications and improper activation of the stress responsive, Slt2 and Hog1 kinases. Thus, we have identified the significance of previously uncharacterized residues of H3 and H4 in DNA damage response, cells cycle progression and cellular aging. This article is protected by copyright. All rights reserved.
PMID: 30536627 [PubMed - as supplied by publisher]
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