Heterogeneous ribonucleoprotein particle
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Heterogeneous nuclear ribonucleoproteins (hnRNPs) are complexes of
RNA Ribonucleic acid (RNA) is a polymeric molecule essential in various biological roles in coding, decoding, regulation and expression of genes. RNA and deoxyribonucleic acid ( DNA) are nucleic acids. Along with lipids, proteins, and carbohydra ...
and
protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...
present in the
cell nucleus The cell nucleus (pl. nuclei; from Latin or , meaning ''kernel'' or ''seed'') is a membrane-bound organelle found in eukaryotic cells. Eukaryotic cells usually have a single nucleus, but a few cell types, such as mammalian red blood cells, h ...
during
gene transcription Transcription is the process of copying a segment of DNA into RNA. The segments of DNA transcribed into RNA molecules that can encode proteins are said to produce messenger RNA (mRNA). Other segments of DNA are copied into RNA molecules calle ...
and subsequent
post-transcriptional modification Transcriptional modification or co-transcriptional modification is a set of biological processes common to most eukaryotic cells by which an RNA primary transcript is chemically altered following transcription from a gene to produce a mature, func ...
of the newly synthesized RNA (pre-mRNA). The presence of the proteins bound to a pre-mRNA molecule serves as a signal that the pre-mRNA is not yet fully processed and therefore not ready for export to the
cytoplasm In cell biology, the cytoplasm is all of the material within a eukaryotic cell, enclosed by the cell membrane, except for the cell nucleus. The material inside the nucleus and contained within the nuclear membrane is termed the nucleoplasm. The ...
. Since most mature RNA is exported from the nucleus relatively quickly, most
RNA-binding protein RNA-binding proteins (often abbreviated as RBPs) are proteins that bind to the double or single stranded RNA in cells and participate in forming ribonucleoprotein complexes. RBPs contain various structural motifs, such as RNA recognition motif ( ...
in the nucleus exist as heterogeneous ribonucleoprotein particles. After splicing has occurred, the proteins remain bound to spliced
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., gene. ...
s and target them for degradation. hnRNPs are also integral to the
40s The eukaryotic small ribosomal subunit (40S) is the smaller subunit of the eukaryotic 80S ribosomes, with the other major component being the large ribosomal subunit (60S). The "40S" and "60S" names originate from the convention that ribosomal pa ...
subunit of the
ribosome Ribosomes ( ) are macromolecular machines, found within all cells, that perform biological protein synthesis (mRNA translation). Ribosomes link amino acids together in the order specified by the codons of messenger RNA (mRNA) molecules to ...
and therefore important for the translation of mRNA in the cytoplasm. However, hnRNPs also have their own
nuclear localization sequence A nuclear localization signal ''or'' sequence (NLS) is an amino acid sequence that 'tags' a protein for import into the cell nucleus by nuclear transport. Typically, this signal consists of one or more short sequences of positively charged lysines o ...
s (NLS) and are therefore found mainly in the nucleus. Though it is known that a few hnRNPs shuttle between the cytoplasm and nucleus, immunofluorescence microscopy with hnRNP-specific
antibodies An antibody (Ab), also known as an immunoglobulin (Ig), is a large, Y-shaped protein used by the immune system to identify and neutralize foreign objects such as pathogenic bacteria and viruses. The antibody recognizes a unique molecule of the ...
shows nucleoplasmic localization of these proteins with little staining in the nucleolus or cytoplasm. This is likely because of its major role in binding to newly transcribed RNAs. High-resolution
immunoelectron microscopy An electron microscope is a microscope that uses a beam of accelerated electrons as a source of illumination. As the wavelength of an electron can be up to 100,000 times shorter than that of visible light photons, electron microscopes have a hi ...
has shown that hnRNPs localize predominantly to the border regions of
chromatin Chromatin is a complex of DNA and protein found in 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 roles in r ...
, where it has access to these nascent RNAs. The proteins involved in the hnRNP complexes are collectively known as heterogeneous ribonucleoproteins. They include protein K and
polypyrimidine tract-binding protein Polypyrimidine tract-binding protein, also known as PTB or hnRNP I, is an RNA-binding protein. PTB functions mainly as a splicing regulator, although it is also involved in alternative 3' end processing, mRNA stability and RNA localization. Two ...
(PTB), which is regulated by
phosphorylation In chemistry, phosphorylation is the attachment of a phosphate group to a molecule or an ion. This process and its inverse, dephosphorylation, are common in biology and could be driven by natural selection. Text was copied from this source, wh ...
catalyzed by
protein kinase A In cell biology, protein kinase A (PKA) is a family of enzymes whose activity is dependent on cellular levels of cyclic AMP (cAMP). PKA is also known as cAMP-dependent protein kinase (). PKA has several functions in the cell, including regulatio ...
and is responsible for suppressing
RNA splicing RNA splicing is a process in molecular biology where a newly-made precursor messenger RNA (pre-mRNA) transcript is transformed into a mature messenger RNA (mRNA). It works by removing all the introns (non-coding regions of RNA) and ''splicing'' b ...
at a particular
exon An exon is any part of a gene that will form a part of the final mature RNA produced by that gene after introns have been removed by RNA splicing. The term ''exon'' refers to both the DNA sequence within a gene and to the corresponding sequen ...
by blocking access of the
spliceosome A spliceosome is a large ribonucleoprotein (RNP) complex found primarily within the nucleus of eukaryotic cells. The spliceosome is assembled from small nuclear RNAs (snRNA) and numerous proteins. Small nuclear RNA (snRNA) molecules bind to specifi ...
to the
polypyrimidine tract {{Short description, A pyrimidine-rich sequence involved in pre-messenger RNA maturation The polypyrimidine tract is a region of pre-messenger RNA (mRNA) that promotes the assembly of the spliceosome, the protein complex specialized for carrying o ...
. hnRNPs are also responsible for strengthening and inhibiting splice sites by making such sites more or less accessible to the spliceosome. Cooperative interactions between attached hnRNPs may encourage certain splicing combinations while inhibiting others.


Role in cell cycle and DNA damage

hnRNPs affect several aspects of the cell cycle by recruiting, splicing, and co-regulating certain cell cycle control proteins. Much of hnRNPs' importance to cell cycle control is evidenced by its role as an oncogene, in which a loss of its functions results in various common cancers. Often, misregulation by hnRNPs is due to splicing errors, but some hnRNPs are also responsible for recruiting and guiding the proteins themselves, rather than just addressing nascent RNAs.


BRCA1

hnRNP C is a key regulator of the
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 h ...
and
BRCA2 ''BRCA2'' and BRCA2 () are a human gene and its protein product, respectively. The official symbol (BRCA2, italic for the gene, nonitalic for the protein) and the official name (originally breast cancer 2; currently BRCA2, DNA repair associated) ...
genes. In response to ionizing radiation, hnRNP C partially localizes to the site of DNA damage, and when depleted,
S-phase S phase (Synthesis Phase) is the phase of the cell cycle in which DNA is replicated, occurring between G1 phase and G2 phase. Since accurate duplication of the genome is critical to successful cell division, the processes that occur during ...
progression of the cell is impaired. Additionally, BRCA1 and BRCA2 levels fall when hnRNP C is lost. BRCA1 and BRCA2 are crucial tumor-suppressor genes which are strongly implicated in breast cancers when mutated. BRCA1 in particular causes G2/M cell cycle arrest in response to DNA damage via the
CHEK1 Checkpoint kinase 1, commonly referred to as Chk1, is a serine/threonine-specific protein kinase that, in humans, is encoded by the ''CHEK1'' gene. Chk1 coordinates the DNA damage response (DDR) and cell cycle checkpoint response. Activation of Chk ...
signaling cascade. hnRNP C is important for the proper expression of other tumor suppressor genes including RAD51 and BRIP1 as well. Through these genes, hnRNP is necessary to induce cell-cycle arrest in response to DNA damage by
ionizing radiation Ionizing radiation (or ionising radiation), including nuclear radiation, consists of subatomic particles or electromagnetic waves that have sufficient energy to ionize atoms or molecules by detaching electrons from them. Some particles can travel ...
.


HER2

HER2 Receptor tyrosine-protein kinase erbB-2 is a protein that in humans is encoded by the ''ERBB2'' gene. ERBB is abbreviated from erythroblastic oncogene B, a gene originally isolated from the avian genome. The human protein is also frequently refer ...
is overexpressed in 20-30% of breast cancers and is commonly associated with poor prognosis. It is therefore an oncogene whose differently spliced variants have been shown to have different functions. Knocking down hnRNP H1 was shown to increase the amount of an oncogenic variant Δ16HER2. HER2 is an upstream regulator of cyclin D1 and p27, and its overexpression leads to the deregulation of the G1/S checkpoint.


p53

hnRNPs also play a role in DNA damage response in coordination with
p53 p53, also known as Tumor protein P53, cellular tumor antigen p53 (UniProt name), or transformation-related protein 53 (TRP53) is a regulatory protein that is often mutated in human cancers. The p53 proteins (originally thought to be, and often s ...
. hnRNP K is rapidly induced after DNA damage by ionizing radiation. It cooperates with p53 to induce the activation of p53 target genes, thus activating cell-cycle checkpoints. p53 itself is an important
tumor-suppressor gene A tumor suppressor gene (TSG), or anti-oncogene, is a gene that regulates a cell during cell division and replication. If the cell grows uncontrollably, it will result in cancer. When a tumor suppressor gene is mutated, it results in a loss or red ...
sometimes known by the epithet “the guardian of the genome.” hnRNP K’s close association with p53 demonstrates its importance in DNA damage control. p53 regulates a large group of RNAs that are not translated into protein, called large intergenic noncoding RNAs ( lincRNAs). p53 suppression of genes is often carried out by a number of these lincRNAs, which in turn have been shown to act though hnRNP K. Through physical interactions with these molecules, hnRNP K is targeted to genes and transmits p53 regulation, thus acting as a key repressor within the p53-dependent transcriptional pathway.


Functions

hnRNP serves a variety of processes in the cell, some of which include: # Preventing the folding of pre-mRNA into secondary structures that may inhibit its interactions with other proteins. # Possible association with the splicing apparatus. # Transport of mRNA out of the nucleus. The association of a pre-mRNA molecule with a hnRNP particle prevents formation of short secondary structures dependent on base pairing of complementary regions, thereby making the pre-mRNA accessible for interactions with other proteins.


CD44 Regulation

hnRNP has been shown to regulate
CD44 The CD44 antigen is a cell-surface glycoprotein involved in cell–cell interactions, cell adhesion and migration. In humans, the CD44 antigen is encoded by the ''CD44'' gene on chromosome 11. CD44 has been referred to as HCAM (homing cell adhesi ...
, a cell-surface
glycoprotein Glycoproteins are proteins which contain oligosaccharide chains covalently attached to amino acid side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known as glycos ...
, through splicing mechanisms. CD44 is involved in cell-cell interactions and has roles in cell adhesion and migration. Splicing of CD44 and the functions of the resulting
isoforms A protein isoform, or "protein variant", is a member of a set of highly similar proteins that originate from a single gene or gene family and are the result of genetic differences. While many perform the same or similar biological roles, some isof ...
are different in breast cancer cells, and when knocked down, hnRNP reduced both cell viability and invasiveness.


Telomeres

Several hnRNPs interact with
telomere A telomere (; ) is a region of repetitive nucleotide sequences associated with specialized proteins at the ends of linear chromosomes. Although there are different architectures, telomeres, in a broad sense, are a widespread genetic feature mos ...
s, which protect the ends of
chromosome A chromosome is a long DNA molecule with part or all of the genetic material of an organism. In most chromosomes the very long thin DNA fibers are coated with packaging proteins; in eukaryotic cells the most important of these proteins are ...
s from deterioration and are often associated with cell longevity. hnRNP D associates with the G-rich repeat region of the telomeres, possibly stabilizing the region from
secondary structures Secondary may refer to: Science and nature * Secondary emission, of particles ** Secondary electrons, electrons generated as ionization products * The secondary winding, or the electrical or electronic circuit connected to the secondary winding ...
which would inhibit telomere replication. hnRNP has also been shown to interact with
telomerase Telomerase, also called terminal transferase, is a ribonucleoprotein that adds a species-dependent telomere repeat sequence to the 3' end of telomeres. A telomere is a region of repetitive sequences at each end of the chromosomes of most euka ...
, the protein responsible for elongating telomeres and prevent their degradation. hnRNPs C1 and C2 associate with the RNA component of telomerase, which improves its ability to access the telomere.


Examples

Human genes encoding heterogeneous nuclear ribonucleoproteins include: *
HNRNPA0 Heterogeneous nuclear ribonucleoprotein A0 is a protein that in humans is encoded by the ''HNRNPA0'' gene. This gene belongs to the A/B subfamily of ubiquitously expressed heterogeneous nuclear ribonucleoproteins ( hnRNPs). The hnRNPs are RNA bi ...
, HNRNPA1, HNRNPA1L1, HNRNPA1L2, HNRNPA3,
HNRNPA2B1 Heterogeneous nuclear ribonucleoproteins A2/B1 is a protein that in humans is encoded by the ''HNRNPA2B1'' gene. Structure ''HNRNPA2B1'' gene contains 12 exons, including a B1 protein specific 36-nucleotide mini-exon. The entire length of intron/ ...
*
HNRNPAB Heterogeneous nuclear ribonucleoprotein A/B, also known as HNRNPAB, is a protein which in humans is encoded by the ''HNRNPAB'' gene. Although this gene is named ''HNRNPAB'' in reference to its first cloning as an RNA binding protein with similarit ...
* HNRNPB1 *
HNRNPC Heterogeneous nuclear ribonucleoproteins C1/C2 is a protein that in humans is encoded by the ''HNRNPC'' gene. It is abnormally expressed in fetuses of both IVF and ICSI, which may contribute to the increase risk of birth defects in these ART. Fu ...
, HNRNPCL1 *
HNRNPD Heterogeneous nuclear ribonucleoprotein D0 (HNRNPD) also known as AU-rich element RNA-binding protein 1 (AUF1) is a protein that in humans is encoded by the ''HNRNPD'' gene. Alternative splicing of this gene results in four transcript variants. ...
(AUF1),
HNRPDL Heterogeneous nuclear ribonucleoprotein D-like, also known as HNRPDL, is a protein which in humans is encoded by the ''HNRPDL'' gene. Function This gene belongs to the subfamily of ubiquitously expressed heterogeneous nuclear ribonucleoprote ...
* HNRNPF * HNRNPG (RBMX) * HNRNPH1, HNRNPH2, HNRNPH3 * HNRNPI (PTB) *
HNRNPK Heterogeneous nuclear ribonucleoprotein K (also protein K) is a protein that in humans is encoded by the ''HNRNPK'' gene. It is found in the cell nucleus that binds to pre-messenger RNA (mRNA) as a component of heterogeneous ribonucleoprotein part ...
*
HNRNPL Heterogeneous nuclear ribonucleoprotein L is a protein that in humans is encoded by the ''HNRNPL'' gene. Function Heterogeneous nuclear RNAs (hnRNAs) which include mRNA precursors and mature mRNAs are associated with specific proteins to form ...
, HNRPLL * HNRNPM * HNRNPP2 (FUS/TLS) *
HNRNPR Heterogeneous nuclear ribonucleoprotein R is a protein that in humans is encoded by the ''HNRNPR'' gene. Function This gene belongs to the subfamily of ubiquitously expressed heterogeneous nuclear ribonucleoproteins (hnRNPs). The hnRNPs are R ...
* HNRNPQ (SYNCRIP) * HNRNPU, HNRNPUL1, HNRNPUL2, HNRNPUL3 *
FMR1 ''FMR1'' (Fragile X Messenger Ribonucleoprotein 1) is a human gene that codes for a protein called ''fragile X messenger ribonucleoprotein'', or FMRP. This protein, most commonly found in the brain, is essential for normal cognitive development ...


See also

* Messenger RNP: complex between mRNA and protein(s) present in nucleus


References


Further reading

* * * * {{DEFAULTSORT:Heterogeneous Ribonucleoprotein Particle Gene expression Ribonucleoproteins