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Excess histone levels mediate cytotoxicity via multiple mechanisms.

Title: Excess histone levels mediate cytotoxicity via multiple mechanisms.
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Name(s): Singh, Rakesh Kumar, author
Liang, Dun, author
Gajjalaiahvari, Ugander Reddy, author
Kabbaj, Marie-Helene Miquel, author
Paik, Johanna, author
Gunjan, Akash, author
Type of Resource: text
Genre: Journal Article
Text
Date Issued: 2010-10-15
Physical Form: computer
online resource
Extent: 1 online resource
Language(s): English
Abstract/Description: The accumulation of excess histone proteins in cells has deleterious consequences such as genomic instability in the form of excessive chromosome loss, enhanced sensitivity to DNA damaging agents and cytotoxicity. Hence, the synthesis of histone proteins is tightly regulated at multiple steps and transcriptional as well as posttranscriptional regulation of histone proteins is well established. Additionally, we have recently demonstrated that histone protein levels are regulated posttranslationally by the DNA damage checkpoint kinase Rad53 and ubiquitin-proteasome dependent proteolysis in the budding yeast. However, the underlying mechanism/s via which excess histones exert their deleterious effects in vivo are not clear. Here we have investigated the mechanistic basis for the deleterious effects of excess histones in budding yeast. We find that the presence of excess histones saturates certain histone modifying enzymes, potentially interfering with their activities. Additionally, excess histones appear to bind non-specifically to DNA as well as RNA, which can adversely affect their metabolism. Microarray analysis revealed that upon overexpression of histone gene pairs, about 240 genes were either up or downregulated by 2-fold or more. Overall, we present evidence that excess histones are likely to mediate their cytotoxic effects via multiple mechanisms that are primarily dependent on inappropriate electrostatic interactions between the positively charged histones and diverse negatively charged molecules in the cell. Our findings help explain the basis for the existence of multiple distinct mechanisms that contribute to the tight control of histone protein levels in cells and highlight their importance in maintaining genomic stability and cell viability.
Identifier: FSU_pmch_20948314 (IID), 10.4161/cc.9.20.13636 (DOI), PMC3055206 (PMCID), 20948314 (RID), 20948314 (EID), 13636 (PII)
Grant Number: R21 MH081046
Publication Note: This NIH-funded author manuscript originally appeared in PubMed Central at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3055206.
Subject(s): Chromatin/chemistry
Chromatin/metabolism
DNA/genetics
DNA/metabolism
Gene Expression Regulation, Fungal
Genomic Instability
Histones/genetics
Histones/metabolism
Microarray Analysis
Nucleic Acid Conformation
Nucleosomes/chemistry
Nucleosomes/metabolism
RNA, Fungal/genetics
RNA, Fungal/metabolism
Saccharomyces cerevisiae/genetics
Saccharomyces cerevisiae/metabolism
Saccharomyces cerevisiae Proteins/genetics
Saccharomyces cerevisiae Proteins/metabolism
Static Electricity
Persistent Link to This Record: http://purl.flvc.org/fsu/fd/FSU_pmch_20948314
Owner Institution: FSU
Is Part Of: Cell cycle (Georgetown, Tex.).
1551-4005
Issue: iss. 20, vol. 9

Choose the citation style.
Singh, R. K., Liang, D., Gajjalaiahvari, U. R., Kabbaj, M. -H. M., Paik, J., & Gunjan, A. (2010). Excess histone levels mediate cytotoxicity via multiple mechanisms. Cell Cycle (Georgetown, Tex.). Retrieved from http://purl.flvc.org/fsu/fd/FSU_pmch_20948314