Histone H2B is one of the 5 main

histone In biology, histones are highly basic proteins abundant in lysine and arginine residues that are found in eukaryotic cell nuclei and in most Archaeal phyla. They act as spools around which DNA winds to create structural units called nucleosomes ...

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...

s involved in the structure of

chromatin Chromatin is a complex of DNA and protein found in eukaryote, eukaryotic cells. The primary function is to package long DNA molecules into more compact, denser structures. This prevents the strands from becoming tangled and also plays important r ...

eukaryotic The eukaryotes ( ) constitute the Domain (biology), domain of Eukaryota or Eukarya, organisms whose Cell (biology), cells have a membrane-bound cell nucleus, nucleus. All animals, plants, Fungus, fungi, seaweeds, and many unicellular organisms ...

cells. Featuring a main globular domain and long

N-terminal The N-terminus (also known as the amino-terminus, NH2-terminus, N-terminal end or amine-terminus) is the start of a protein or polypeptide, referring to the free amine group (-NH2) located at the end of a polypeptide. Within a peptide, the amin ...

and

C-terminal The C-terminus (also known as the carboxyl-terminus, carboxy-terminus, C-terminal tail, carboxy tail, C-terminal end, or COOH-terminus) is the end of an amino acid chain (protein or polypeptide), terminated by a free carboxyl group (-COOH). When t ...

tails, H2B is involved with the structure of the

nucleosome A nucleosome is the basic structural unit of DNA packaging in eukaryotes. The structure of a nucleosome consists of a segment of DNA wound around eight histone, histone proteins and resembles thread wrapped around a bobbin, spool. The nucleosome ...

Structure

Histone tails and their function in chromatin formation

Histone H2B is a lightweight structural protein made of 126

amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although over 500 amino acids exist in nature, by far the most important are the 22 α-amino acids incorporated into proteins. Only these 22 a ...

s. Many of these

s have a positive charge at cellular pH, which allows them to interact with the negatively charged phosphate groups in

DNA Deoxyribonucleic acid (; DNA) is a polymer composed of two polynucleotide chains that coil around each other to form a double helix. The polymer carries genetic instructions for the development, functioning, growth and reproduction of al ...

. Along with a central globular domain, histone H2B has two flexible histone tails that extend outwards – one at the N-terminal end and one at C-terminal end. These are highly involved in condensing

from the beads-on-a-string conformation to a 30-nm fiber. Similar to other

s, histone H2B has a distinct histone fold that is optimized for histone-histone as well as histone-DNA interactions. Two copies of histone H2B come together with two copies each of

histone H2A Histone H2A is one of the five main histone proteins involved in the structure of chromatin in eukaryotic cells. The other histone proteins are: Histone H1, H1, Histone H2B, H2B, Histone H3, H3 and Histone H4, H4. Background Histones are pro ...

histone H3 Histone H3 is one of the five main histones involved in the structure of chromatin in eukaryotic cells. Featuring a main globular domain and a long N-terminal end, N-terminal tail, H3 is involved with the structure of the nucleosomes of the 'b ...

, and

histone H4 Histone H4 is one of the five main histone proteins involved in the structure of chromatin in eukaryote, eukaryotic cells. Featuring a main globular domain and a long N-terminus, N-terminal tail, H4 is involved with the structure of the nucleo ...

to form the octamer core of the nucleosome to give structure to

. To facilitate this formation, histone H2B first binds to

to form a heterodimer. Two of these heterodimers then bind together with a heterotetramer made of

and

, giving the

its characteristic disk shape.

is then wrapped around the entire nucleosome in groups of approximately 160 base pairs of

. The wrapping continues until all

has been packaged with the nucleosomes.

Function

Histone H2B is a structural

that helps organize eukaryotic

. It plays an important role in the biology of the nucleus where it is involved in the packaging and maintaining of

chromosome A chromosome is a package of DNA containing part or all of the genetic material of an organism. In most chromosomes, the very long thin DNA fibers are coated with nucleosome-forming packaging proteins; in eukaryotic cells, the most import ...

s, regulation of transcription, and replication and

repair The technical meaning of maintenance involves functional checks, servicing, repairing or replacing of necessary devices, equipment, machinery, building infrastructure and supporting utilities in industrial, business, and residential installat ...

of DNA. Histone H2B helps regulate

structure and function through post-translational modifications and specialized histone variants. Acetylation and

ubiquitin Ubiquitin is a small (8.6 kDa) regulatory protein found in most tissues of eukaryotic organisms, i.e., it is found ''ubiquitously''. It was discovered in 1975 by Gideon Goldstein and further characterized throughout the late 1970s and 19 ...

ation are examples of two post-translational modifications that affect the function of histone H2B in particular ways. Hyperacetylation of histone tails helps DNA-binding proteins access

by weakening histone-DNA and nucleosome-nucleosome interactions. Furthermore, acetylation of a specific

lysine Lysine (symbol Lys or K) is an α-amino acid that is a precursor to many proteins. Lysine contains an α-amino group (which is in the protonated form when the lysine is dissolved in water at physiological pH), an α-carboxylic acid group ( ...

residue binds to bromine-containing domains of certain transcription and chromatin regulatory

s. This docking facilitates the recruitment of these proteins to the correct region of the

. Ubiquitinated histone H2B is often found in regions of active transcription. Through the facilitation of

chromatin remodeling Chromatin remodeling is the dynamic modification of chromatin architecture to allow access of condensed genomic DNA to the regulatory transcription machinery proteins, and thereby control gene expression. Such remodeling is principally carried out ...

, it stimulates transcriptional elongation and sets the stage for further modifications that regulate multiple elements of transcription. Specifically, the ubiquitin on histone H2B opens up and unfolds regions of

allowing transcription machinery access to the promoter and coding regions of

. While only a few

isoforms A protein isoform, or "protein variant", is a member of a set of highly similar proteins that originate from a single gene and are the result of genetic differences. While many perform the same or similar biological roles, some isoforms have uniqu ...

of histone H2B have been studied in depth, researchers have found that histone H2B variants serve important roles. If certain variants stopped functioning, centromeres would not form correctly, genome integrity would be lost, and the DNA damage response would be silenced. Specifically, in some lower

eukaryote The eukaryotes ( ) constitute the Domain (biology), domain of Eukaryota or Eukarya, organisms whose Cell (biology), cells have a membrane-bound cell nucleus, nucleus. All animals, plants, Fungus, fungi, seaweeds, and many unicellular organisms ...

s, a histone H2B variant binds to a

variant called H2AZ, localizes to active

gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...

s, and supports transcription in those regions. In mice, a variant called H2BE helps control the expression of olfactory

s. This supports the idea that

of histone H2B may have specialized functions in different tissues.

DNA damage response

Ubiquitin Ubiquitin is a small (8.6 kDa) regulatory protein found in most tissues of eukaryotic organisms, i.e., it is found ''ubiquitously''. It was discovered in 1975 by Gideon Goldstein and further characterized throughout the late 1970s and 19 ...

ation of histone H2B in response to DNA damage is important for timely initiation of

DNA repair DNA repair is a collection of processes by which a cell (biology), cell identifies and corrects damage to the DNA molecules that encode its genome. A weakened capacity for DNA repair is a risk factor for the development of cancer. DNA is cons ...

.Uckelmann M, Sixma TK. Histone ubiquitination in the DNA damage response. DNA Repair (Amst). 2017 Aug;56:92-101. doi: 10.1016/j.dnarep.2017.06.011. Epub 2017 Jun 9. PMID 28624371 Ubiquitinase RNF20/RNF40 specifically modifies histone H2B at position K120 and this modification is need for recruitment to damaged DNA of the factors necessary for repair by the pathways of

homologous recombination Homologous recombination is a type of genetic recombination in which genetic information is exchanged between two similar or identical molecules of double-stranded or single-stranded nucleic acids (usually DNA as in Cell (biology), cellular organi ...

and

non-homologous end joining Non-homologous end joining (NHEJ) is a pathway that repairs double-strand breaks in DNA. It is called "non-homologous" because the break ends are directly ligated without the need for a homologous template, in contrast to homology directed repair ...

Isoforms

There are sixteen variants of histone H2B found in humans, thirteen of which are expressed in regular body cells and three of which are only expressed in the testes. These variants, also called

, are proteins that are structurally very similar to the regular histone H2B but feature some specific variations in their

sequence. All variants of histone H2B contain the same number of

s, and the variations in sequence are few in number. Only two to five

s are changed, but even these small differences can alter the

higher level structure. Histone H2B isoforms interact differently with other

s, are found in specific regions of

, have different types and numbers of post-translational modifications, and are more or less stable than regular histone H2B. All of these differences accumulate and cause the

to have unique functions and even function differently in different tissues. Many histone H2B

are expressed in a

DNA replication In molecular biology, DNA replication is the biological process of producing two identical replicas of DNA from one original DNA molecule. DNA replication occurs in all life, living organisms, acting as the most essential part of heredity, biolog ...

independent manner. They are produced at the same level during all phases of the

cell cycle The cell cycle, or cell-division cycle, is the sequential series of events that take place in a cell (biology), cell that causes it to divide into two daughter cells. These events include the growth of the cell, duplication of its DNA (DNA re ...

. Regular histone H2B is only added to

s during the

S-phase S phase (Synthesis phase) is the phase of the cell cycle in which DNA is DNA replication, replicated, occurring between G1 phase, G1 phase and G2 phase, G2 phase. Since accurate duplication of the genome is critical to successful cell division, ...

of the

when

is replicated; histone H2B

can be added to

s at other times during the

. Histone variants of H2B can be explored usin
"HistoneDB with Variants" database.

Post-Translational Modifications

Histone H2B is modified by a combination of several types of post-translational modifications. These modifications affect the structural and functional organization of

, and the majority of them are found outside the globular domain of the

where

residues are more accessible. Possible modifications include acetylation, methylation, phosphorylation, ubiquitination, and sumoylation. Acetylation, phosphorylation, and ubiquitination are the most common and most studied modifications of histone H2B.

Acetylation

Histone H2B proteins found both in the promoter and coding regions of

s contain specific patterns of hyperacetylation and hypoacetylation on certain

residues found in the N-terminal tail. Acetylation relies on specific

acetyltransferases that work at gene promoters during transcriptional activation. Adding an acetyl group to

residues in one of several positions in the

tail contributes to the activation of transcription. In fact, scientists consider acetylation of histone H2B's N-terminal tails, such as H2BK5ac, to be an extremely important part of regulating

transcription.

''O''-GlcNAcylation

Modification of H2B S112 with ''O''-GlcNAc is thought to facilitate monoubiquitination of K112, which in turn is associated with transcriptionally activated regions.

Phosphorylation

In histone H2B, a phosphorylated

serine Serine (symbol Ser or S) is an α-amino acid that is used in the biosynthesis of proteins. It contains an α- amino group (which is in the protonated − form under biological conditions), a carboxyl group (which is in the deprotonated − ...

threonine Threonine (symbol Thr or T) is an amino acid that is used in the biosynthesis of proteins. It contains an α-amino group (which is in the protonated −NH form when dissolved in water), a carboxyl group (which is in the deprotonated −COO− ...

residue activates transcription. When a cell experiences metabolic stress, an

AMP-activated protein kinase 5' AMP-activated protein kinase or AMPK or 5' adenosine monophosphate-activated protein kinase is an enzyme (EC 2.7.11.31) that plays a role in cellular energy homeostasis, largely to activate glucose and fatty acid uptake and oxidation when cell ...

phosphorylates the

at position 36 in histone H2B of the promoter and coding regions on

, which helps regulate transcriptional elongation. If cells receive multiple apoptotic stimuli, caspase-3 activates the Mst1 kinase, which phosphorylates the

at position 14 in all histone H2B proteins, which helps facilitate chromatin condensation.

DNA damage DNA repair is a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encode its genome. A weakened capacity for DNA repair is a risk factor for the development of cancer. DNA is constantly modified ...

can induce this same response on a more localized scale very quickly to help facilitate

Ubiquitination

Ubiquitin residues are usually added to the

at position 120 on histone H2B. Ubiquitinating this

residue activates transcription. Scientists have discovered other ubiquitination sites in recent years, but they are not well studied or understood at this time. Ubiquitin-conjugating

enzyme An enzyme () is a protein that acts as a biological catalyst by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different mol ...

s and ubiquitin

ligase In biochemistry, a ligase is an enzyme that can catalyze the joining ( ligation) of two molecules by forming a new chemical bond. This is typically via hydrolysis of a small pendant chemical group on one of the molecules, typically resulting i ...

s regulate the ubiquitination of histone H2B. These enzymes use co-transcription to conjugate ubiquitin to histone H2B. Histone H2B's level of ubiquitination varies throughout the

. All ubiquitin moieties are removed from histone H2B during

metaphase Metaphase ( and ) is a stage of mitosis in the eukaryotic cell cycle in which chromosomes are at their second-most condensed and coiled stage (they are at their most condensed in anaphase). These chromosomes, carrying genetic information, alig ...

and re-conjugated during

anaphase Anaphase () is the stage of mitosis after the process of metaphase, when replicated chromosomes are split and the newly-copied chromosomes (daughter chromatids) are moved to opposite poles of the cell. Chromosomes also reach their overall maxim ...

Genetics

Histone H2B's

sequence is highly evolutionarily conserved. Even distantly related species have extremely similar histone H2B proteins. The histone H2B family contains 214 members from many different and diverse species. In humans, histone H2B is coded for by twenty-three different

s, none of which contain

intron An intron is any nucleotide sequence within a gene that is not expressed or operative in the final RNA product. The word ''intron'' is derived from the term ''intragenic region'', i.e., a region inside a gene."The notion of the cistron .e., gen ...

s. All of these

s are located in

cluster 1 on

chromosome 6 Chromosome 6 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 6 spans nearly 171 million base pairs (the building material of DNA) and represents between 5.5 and 6% of the total DNA i ...

and cluster 2 and cluster 3 on

chromosome 1 Chromosome 1 is the designation for the largest human chromosome. Humans have two copies of chromosome 1, as they do with all of the autosomes, which are the non-sex chromosomes. Chromosome 1 spans about 249 million nucleotide base pairs, which a ...

. In each

cluster, histone H2B genes share a promoter region with sequences that code for

. While all

s in the

cluster are transcribed at high levels during

, individual histone H2B genes are also expressed at other times during the

. They are dually regulated by the cluster promoter sequences and their specific promoter sequences.

References

{{reflist Proteins DNA-binding proteins