Abstract
Histone variants are chromatin components that replace replication-coupled histones in a fraction of nucleosomes and confer particular characteristics to chromatin. H2A variants represent the most numerous and diverse group among histone protein families. In the nucleosomal structure, H2A-H2B dimers can be removed and exchanged more easily than the stable H3-H4 core. The unstructured N-terminal histone tails of all histones, but also the C-terminal tails of H2A histones protrude out of the compact structure of the nucleosome core. These accessible tails are the preferential target sites for a large number of post-translational modifications (PTMs). While some PTMs are shared between replication-coupled H2A and H2A variants, many modifications are limited to a specific histone variant. The present review focuses on the H2A variants H2A.Z, H2A.X, and macroH2A, and summarizes their functions in chromatin and how these are linked to cancer development and progression. H2A.Z primarily acts as an oncogene and macroH2A and H2A.X as tumour suppressors. We further focus on the regulation by PTMs, which helps to understand a degree of context dependency.
Highlights
The nucleosome particle is the basic unit of the chromatin fibre
Loss of macroH2A1 leads to the acquisition of stem-like features and gene expression programs, which include LIN28A transcription in bladder cancer and increased NF-Kb signalling in hepatocellular carcinoma [149,195]
The substitution of replication-coupled H2A by one of its variants represents an epigenetic regulation mechanism that impacts virtually all of the processes occurring in chromatin, and is highly relevant in many physiological contexts
Summary
The nucleosome particle is the basic unit of the chromatin fibre. The nucleosome consists of a histone octamer core around which 147bp of DNA are wrapped about 1.7 times. Covalent modifications of core histones have the potential to alter the properties of the nucleosome or the ability of protein effectors to interact with it, acting as essential regulators of chromatin function [5]. The replacement of replication-coupled core histones by histone variants provides chromatin with specific characteristics and can influence all functions occurring on the chromatin template including transcription and DNA repair [8,9] This occurs through different mechanisms that include: alteration of the biophysical properties of the nucleosome [10], promoting the deposition of certain histone modifications or recruitment of specific interactors [8]. Post-translational modifications (PTMs) are an essential and highly dynamic mechanism for the regulation of protein function and the transduction and integration of signals in the cell [16]. Data bank ID 3REH [20] and generated with ProteinWorkshop [21], the picture of the macroH2A macrodomain is based on PDB ID 2FXK [22] and generated with NGL viewer [23,24]
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