GLD-2

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TENT2
Gene ontology
Molecular function	transferase activity nucleotide binding polynucleotide adenylyltransferase activity protein binding ATP binding metal ion binding 5'-3' RNA polymerase activity adenylyltransferase activity
Cellular component	nuclear RNA-directed RNA polymerase complex cytoplasm cytosol nucleus
Biological process	histone mRNA catabolic process mRNA processing RNA polyadenylation hematopoietic progenitor cell differentiation hippocampus development neuron differentiation retina development in camera-type eye dark adaptation RNA stabilization negative regulation of miRNA catabolic process
Sources:Amigo / QuickGO

Ensembl				ENSG00000164329	n/a
UniProt	Q6PIY7	Q91YI6
RefSeq (mRNA)	NM_001114393 NM_001114394 NM_001297744 NM_001297745 NM_173797 NM_001349548 NM_001349549 NM_001349550 NM_001349551 NM_001349552 NM_001349553 NM_001349554	NM_133905 NM_001361536 NM_001361537
RefSeq (protein)	NP_001107865 NP_001107866 NP_001284673 NP_001284674 NP_776158 NP_001336477 NP_001336478 NP_001336479 NP_001336480 NP_001336481 NP_001336482 NP_001336483	NP_598666 NP_001348465 NP_001348466
Location (UCSC)	Chr 5: 79.61 – 79.69 Mb	n/a
PubMed search	[2]	[3]

Wikidata

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GLD-2 (which stands for Germ Line Development 2) is a cytoplasmic poly(A) polymerase (cytoPAPs) which adds successive AMP monomers to the 3’ end of specific RNAs, forming a poly(A) tail, which is a process known as polyadenylation.

For RNA specificity, GLD-2 associates with an RNA-binding protein, typically a GLD-3, to form a

that acts as a cytoplasmic PAP. This protein has an enzymatic function and belongs to a family (DNA polymerase type-B-like family) which includes several similar enzymes such as GLD-1, GLD-3 and GLD-4.

This family of cytoplasmic PAPs has been described in several different species including

. Moreover, as it is a cytoplasmtaic PAP it differs from nuclear PAPs in some aspects. While nuclear PAPs contain a catalytic domain and an RNA-binding domain, GLD-2 family members have only a catalytic domain.

Localization

GLD-2 is a common and abundant, but yet quite unknown protein that has already been found in each of the

Escherichia Coli

in monera and Candida albicans in fungi.

In human beings it is mostly expressed in the brain and within it, in the cerebellum, hippocampus and medulla. We can also find them in some other source tissues are the fibroblast, HeLa cell, MCF-7 cell, melanoma cell line and

mitochondrion

since its main function is related with DNA polyadenilation and these cell organelles are the only ones were DNA can be found. However, there are also GLD-2 in a soluble way in the cytosol, although the reason why they are there is still unsure.

In Escherichia Coli, this enzymatic protein can be found in the cell membrane and in the cytosol, whereas in Drosophila melanogaster, it predominates in the brain's nucleus and cytoplasm, oocyte, ovary and testis’ cells. Finally, in the Arabidopsis thaliana, it is located in the flower's nucleus, root, stem and leaf cells.

Related functions

GLD-2 primarily stabilizes mRNAs that are translationally repressed as well as it strongly promotes bulk polyadenylation. Surprisingly, those functions seem to have little impact on dynamizing efficient target mRNA translation, as it is an efficient Poly(A) Polymerase which helps developing polyadenylation activity. This activity is stimulated by its interaction with a putative RNA-binding protein: GLD-3. It is proposed by some studies that GLD-3 stimulates GLD-2 by recruiting it to the RNA. If so, then bringing GLD-2 to the RNA by other means also should stimulate its activity.

Molecular function

ATP binding

GLD-2, as a poly(A) polymerase (PAP) acts incorporating ATP at the 3' end of mRNAs in a template-independent manner.

Enzymatic activity: Polynucleotide adenylyltransferase activity

It has been discovered that this protein has a catalytic activity, in other words, it has the ability to increase the speed of chemical reactions which would not occur so fast. It is known to

the following reaction (which requires the following cofactor: Mg(2+)):

                            ATP + RNA(n)  ⇄  diphosphate  +  RNA(n+1)

Depending on the surroundings the optimal pH varies from 8 in the cytoplasm to 8.3 in the nucleus.

Biological process

Hematopoietic progenitor cell differentiation

The GLD-2 protein together with 136 proteins more, is involved in the molecular process of

progenitor cell differentiation, in the human proteome. This is the process in which precursor cell type acquires the specialized features of a hematopoietic progenitor cell, a kind of cell types including myeloid progenitor cells and lymphoid progenitor cells.

mRNA processing by RNA polyadenylation

The polyadenylation activity of GLD-2, as we previously mentioned, is stimulated by physical interaction with an RNA binding protein, GLD-3. To test whether GLD-3 might stimulate GLD-2 by recruiting it to RNA, some studies tethered C. elegans GLD-2 to mRNAs in Xenopus

by using MS2 coat protein. Tethered GLD-2 adds poly(A) and stimulates translation of the mRNA, demonstrating that recruitment is sufficient to stimulate polyadenylation activity. PAP heterodimer in which GLD-2 contains the active site and GLD-3 provides RNA-binding specificity. MS2 coat protein was joined to GLD-2 to recruit it to an RNA.

Furthermore, GLD-2 activity is also important to maintain or up-regulate the abundance of many mRNAs, as the cytoplasmic polyadenylation has an essential role in activating maternal

, the reaction requires CPEB, an RNA-binding protein and the poly(A) polymerase GLD-2.

The Xenopus enzyme, which exists in two closely related forms, polyadenylates RNAs to which it is tethered and enhances their translation. Likewise, it interacts with cytoplasmic polyadenylation factors, including

, and with target mRNAs. These findings confirm and extend a recent report that a GLD-2 enzyme is the long-sought PAP responsible for cytoplasmic polyadenylation in oocytes.

In addition, the formation of long-term memory is believed to lack translational control of localized mRNAs. In mammals, dendrite mRNAs are kept in a repressed state and are activated upon repetitive stimulation. Several regulatory proteins required for translational control in early development are thought to be needed for memory formation, suggesting similar molecular mechanisms. In an experiment using Drosophila, it has been detected the enzyme responsible for poly(A) elongation in the brain and it has been demonstrated too that its activity is required specifically for long-term memory. These findings provide strong evidence that cytoplasmic polyadenylation is critical for memory formation, and that GLD2 is the responsible enzyme.

Medical implications

It has also been discovered that GLD2 has medical uses.

For example, such enzyme is overexpressed in patients who suffer from cancer; that's why it can be used as a prognostic factor for early appearance in breast cancer patients. Moreover, PAP activity is used to measure the effect of anticancer drugs as etoposide and cordycepin in two carcinoma cell lines: HeLa, which is the human epithelioid cervix carcinoma, and MCF-7 (human breast cancer). However, in spite its utilities it can also be involved in the expression of several common diseases such as:

and in some cases infertility in male patients.

References

Further reading