Sandbox GGC1

Introduction

Histone H3.3 is a variant histone of H3 which has the gene name H3.3A and this particular protein is found in Humans. The location of this can be found in the nucleus and in the chromosome.^[1]

Function

Histone H3 replaces H3 in a range of nucleosomes in active genes and it takes over the original H3 in non dividing cells. Nucleosomes wrap around and compact DNA into chromatin which limits DNA access to cellular machineries which need DNA as a template. Histones play an important role in regulation of transcription, DNA repair, DNA replication and also chromosomal stability. Access to DNA is regulated by post-translational modifications of histones which is called a histone code, and nucleosome remodeling. It also serves as a replacement histone that's imbedded chromatin regions by the HIRA chaperone, after the depletion of the H3.1 during transcription and DNA repair.^[2]

Disease

There have been studies that have identified mutations encoding a K27M substitution and there have also been mutations that encoded GLY 34 to ARG or VAL called the G34R/V substitution. K27M tumors are present in ex: spinal cord, thalamus, pons, brainstem and G34R/V tumors are shown in the cerebral hemispheres. There are mutations in H3.3 that are found in different types of bone tumors like chrondroblastoma for example and giant cell tumors of the bone. Chondroblastomaarises in children and in young adults in the cartilage of the growth plates of the long bones and is most typically benign.

Glioma is another disease caused by the H3F3A mutation, however they are benign or either malignant central nervous system of abnormal growth of tissue from glial cells.

Relevance

Histone octamer containing two of H2A, H2B, H3 and H4 and the octamer wraps 147bp of DNA. H3.3 interacts with HIRA which is a chaperone and ZMYND11 when trimethylated at (color coded dark blue)^[3]. HIRA can deposit histones of H3.3 in replicating and non replicating cells. Also in the HIRA complex, Anti slicing factors ASF1a and ASF1b are purified by H3.3. However, when there's a disappearance of HIRA which is responsible for H3.3 deposition, it can cause defects in the early stages of embryogenesis. ZMYND11 also known as BS69 can find H3.3 LYS 36 (H3.3K36me3) by the binding domain of chromatin ^[4].

Structural highlights

CENP-Ais a centromere specific variant of Histone H3 and it's controlled in normal cells and its chromosome localization is heavily restricted in the centromere regions. It can be over expressed in cancer cells and also be mislocalized ectopically in the form of heterotypic nucleosomes containing H3.3 ^[5]. In vitro, the human CENP-A nucleosomes can have two copies each of CENP-A, H2A, H2B and H4 histones ^[6]. is located on H3.3 and is on the E chain (color coded light pink). The significance to this is that ARG 49 of Asf1 is maintained as threonine or glutamic acid. Histone H2B located on chains D and H (color coded dark blue), histone H2A type 1-B/E which is located chains C and G (also color coded dark blue),Histone H3-like centromeric protein A is located on chain A (color coded in the lightest blue),and Histone H4 is located on chains B and F (color coded medium blue) ^[7].