Histone-binding protein RBBP4 (also known as RbAp48, or NURF55) is a
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 ...
that in humans is encoded by the ''RBBP4''
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 ...
.
Function
This gene encodes a ubiquitously expressed nuclear protein that belongs to a highly conserved subfamily of
WD-repeat proteins. It is present in protein complexes involved in
histone acetylation and
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 ...
assembly. It is part of the
Mi-2/NuRD complex that has been implicated in
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 ...
and transcriptional repression associated with histone deacetylation. This encoded protein is also part of
corepressor
In genetics and molecular biology, a corepressor is a molecule that represses the expression of genes. In prokaryotes
A prokaryote (; less commonly spelled procaryote) is a single-celled organism whose cell lacks a nucleus and other membra ...
complexes, which is an integral component of transcriptional silencing. It is found among several cellular proteins that bind directly to
retinoblastoma protein
Retinoblastoma (Rb) is a rare form of cancer that rapidly develops from the immature cells of a retina, the light-detecting tissue of the eye. It is the most common primary malignant intraocular cancer in children, and 80% of retinoblastoma cas ...
to regulate cell proliferation. This protein also seems to be involved in transcriptional repression of
E2F-responsive genes.
Clinical significance
A decrease of RbAp48 in the
dentate gyrus
The dentate gyrus (DG) is one of the subfields of the hippocampus, in the hippocampal formation. The hippocampal formation is located in the temporal lobe of the brain, and includes the hippocampus (including CA1 to CA4) subfields, and other su ...
(DG) of the
hippocampus
The hippocampus (: hippocampi; via Latin from Ancient Greek, Greek , 'seahorse'), also hippocampus proper, is a major component of the brain of humans and many other vertebrates. In the human brain the hippocampus, the dentate gyrus, and the ...
in the
brain
The brain is an organ (biology), organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. It consists of nervous tissue and is typically located in the head (cephalization), usually near organs for ...
is suspected to be a main cause of
memory loss
Amnesia is a deficit in memory caused by brain damage or brain diseases,Gazzaniga, M., Ivry, R., & Mangun, G. (2009) Cognitive Neuroscience: The biology of the mind. New York: W.W. Norton & Company. but it can also be temporarily caused by t ...
in normal
aging
Ageing (or aging in American English) is the process of becoming Old age, older until death. The term refers mainly to humans, many other animals, and fungi; whereas for example, bacteria, perennial plants and some simple animals are potentiall ...
.
An age related decrease in RbAp48 is observed in the DG from human post-mortem tissue and also in mice. Furthermore, a
gene knockin of a
dominant negative form of RbAp48 of causes memory deficits in young mice similar to that observed in older mice. Using
lentiviral gene transfer to increase the expression of RbAp48 in the brain reverses memory deficits in older mice.
RBBP4 works at least in part through the
PKA
In chemistry, an acid dissociation constant (also known as acidity constant, or acid-ionization constant; denoted ) is a quantitative measure of the strength of an acid in solution. It is the equilibrium constant for a chemical reaction
:H ...
-
CREB1-
CPB pathway.
Hence one possible therapeutic approach to restore age-related memory loss is the use of PKA-CREB1-CPB pathway stimulating drugs. It has previously been shown that dopamine D1/D5 agonists such as
6-Br-APB and
SKF-38,393 that are positively coupled to
adenylyl cyclase
Adenylate cyclase (EC 4.6.1.1, also commonly known as adenyl cyclase and adenylyl cyclase, abbreviated AC) is an enzyme with systematic name ATP diphosphate-lyase (cyclizing; 3′,5′-cyclic-AMP-forming). It catalyzes the following reaction:
:A ...
and the
cAMP phosphodieserase inhibitor
rolipram
Rolipram is a selective phosphodiesterase-4 inhibitor discovered and developed by Schering AG as a potential antidepressant drug in the early 1990s. It served as a prototype molecule for several companies' drug discovery and development efforts ...
reduce memory defects in aged mice.
Interactions
RBBP4 has been shown to
interact with:
*
BRCA1
Breast cancer type 1 susceptibility protein is a protein that in humans is encoded by the ''BRCA1'' () gene. Orthologs are common in other vertebrate species, whereas invertebrate genomes may encode a more distantly related gene. ''BRCA1'' is a ...
,
*
CREBBP,
*
GATAD2B,
*
HDAC1
Histone deacetylase 1 (HDAC1) is an enzyme that in humans is encoded by the ''HDAC1'' gene.
Function
Histone acetylation and deacetylation, catalyzed by multisubunit complexes, play a key role in the regulation of eukaryotic gene expression. ...
,
*
HDAC2
Histone deacetylase 2 (HDAC2) is an enzyme that in humans is encoded by the ''HDAC2'' gene. It belongs to the histone deacetylase class of enzymes responsible for the removal of acetyl groups from lysine residues at the N-terminal region of the ...
,
HDAC3
Histone deacetylase 3 is an enzyme encoded by the ''HDAC3'' gene in both humans and mice.
Function
Histones are highly alkaline proteins that package and order DNA into structural units called nucleosomes, which comprise the major protein comp ...
,[
* ]MTA2
Metastasis-associated protein MTA2 is a protein that in humans is encoded by the ''MTA2'' gene.
MTA2 is the second member of the MTA family of genes. MTA2 protein localizes in the nucleus and is a component of the nucleosome remodeling and the ...
,[
* RB,]SIN3A
Paired amphipathic helix protein Sin3a is a protein that in humans is encoded by the ''SIN3A'' gene.
Function
The protein encoded by this gene is a transcriptional regulatory protein. It contains paired amphipathic helix (PAH) domains, whic ...
.
References
Further reading
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
{{Refend