Abstract
Replication-dependent histones are expressed in a cell cycle regulated manner and supply the histones necessary to support DNA replication. In mammals, the replication-dependent histones are encoded by a family of genes that are located in several clusters. In humans, these include 16 genes for histone H2A, 22 genes for histone H2B, 14 genes for histone H3, 14 genes for histone H4 and 6 genes for histone H1. While the proteins encoded by these genes are highly similar, they are not identical. For many years, these genes were thought to encode functionally equivalent histone proteins. However, several lines of evidence have emerged that suggest that the replication-dependent histone genes can have specific functions and may constitute a novel layer of chromatin regulation. This Survey and Summary reviews the literature on replication-dependent histone isoforms and discusses potential mechanisms by which the small variations in primary sequence between the isoforms can alter chromatin function. In addition, we summarize the wealth of data implicating altered regulation of histone isoform expression in cancer.
Highlights
Nucleosomes are highly dynamic structures, comprising 146 base pairs of DNA wrapped about 1.7 turns around an octameric histone core in a left-hand orientation
Nucleosome structure is vital for regulation of gene expression and many other DNA-dependent processes including transcription, replication, recombination, and repair
We provide an overview of the existing literature about these isoforms and discuss their potential role in carcinogenesis
Summary
Nucleosomes are highly dynamic structures, comprising 146 base pairs of DNA wrapped about 1.7 turns around an octameric histone core in a left-hand orientation. The core histone tail domains are required for the assembly of higherorder structures and affect histone interactions with nonhistone proteins as well as histone-histone and histoneDNA interactions [3,8,10,11] These modifications, including acetylation, ubiquitination, phosphorylation, methylation, sumoylation and ADP-ribosylation alter the structure and dynamics of the nucleosome, and modulate chromosome function. The nonhistone domain containing variant, macroH2A, is enriched on the transcriptionally inactivated female X chromosome, senescence-associated heterochromatic foci (SAHF), and other transcriptionally silent domains Overall, many of these variants function as an ensemble, and any alterations in their localization and distribution can affect the higherorder chromatin organization, compromising mitotic progression and genome stability [32,33]
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