WRAP53 (also known as WD40-encoding RNA antisense to p53) is a gene implicated in cancer development. The name was coined in 2009 to describe the dual role of this gene, encoding both an antisense RNA that regulates the p53 tumor suppressor and a protein involved in DNA repair, telomere elongation and maintenance of nuclear organelles Cajal bodies (Figure 1). [5] [6] [7] [8]
The WRAP53 gene is localized on chromosome 17p13.1 and contains 13 exons, including three alternative starting exons (1α, 1β and 1γ) generating at least three gene products. The WRAP53 gene partially overlaps the p53 tumor suppressor gene in a head-to-head orientation.
Transcripts of WRAP53 that overlap the first exon of p53 (referred to as WRAP53α transcripts) regulate the levels of p53 mRNA and protein (Figure 1). [5] [9] WRAP53γ transcripts overlap the first intron of p53 and are antisense to the previously identified transcript Hp53int1 localized within this intron. However, the function of WRAP53γ remains elusive.
The WRAP53 gene also encodes a protein termed WRAP53β (alias WRAP53 or WDR79 or TCAB1), which belongs to the WD40 protein family (Figure 1). WRAP53β facilitates protein-protein and protein-RNA interactions and directs factors to nuclear organelles Cajal bodies, to telomeres and to DNA double-strand breaks. [7] [8] [10] [11] Factors localized to Cajal bodies with the help of WRAP53β includes the SMN protein, [10] small Cajal body-specific scaRNAs [8] and the enzyme telomerase. [7] WRAP53β also targets the ubiquitin ligase RNF8 to DNA double-strand breaks [11] (Figure 2).
In addition to localizing factors to correct cellular sites, WRAP53β maintain structural integrity of Cajal bodies and without WRAP53β these organelles collapse and cannot re-form [10] (Figure 2).
The WRAP53β protein is highly evolutionary conserved, with homologs (confined to its WD40 repeats) in vertebrates, invertebrates, plants and yeast. [5] [12] [13] WRAP53β consists of a proline-rich N-terminus, a central WD40 domain and a glycine-rich C-terminus (Figure 3). The WD40 domain of WRAP53β serves as a scaffold for multiple interactions between a wide variety of molecules.
Germline mutations in WRAP53β result in disorder known as dyskeratosis congenita, characterized by bone marrow failure, premature ageing, predisposition for cancer and a triad of mucocutaneous features including oral leukoplakia, abnormal skin pigmentation and nail dystrophy. [13] Mutations in WRAP53β are inherited in an autosomal recessive fashion, reside in highly conserved regions of its WD40 domain and result in a more severe form of this disease. [14] [15]
These mutations reduce the nuclear level of WRAP53β, impair its trafficking of telomerase to telomeres, and subsequently lead to progressive shortening of telomeres in these patients [13] The chaperonin CCT/TRiC is crucial for proper folding of WRAP53β and this folding is impaired in dyskeratosis congenita [16]
Defective WRAP53β-mediated trafficking of SMN is observed in patients afflicted by the most severe form of spinal muscular atrophy (type I or Werdnig-Hoffmann disease), [17] [18] a neurodegenerative disorder characterized by progressive degeneration of spinal cord anterior horn α-motor neurons and the leading genetic cause of infant mortality with an incidence of approximately 1:6000 live births. [19] Mutations in the SMN1 gene are the underlying cause to spinal muscular atrophy (SMA).
WRAP53β is overexpressed in a variety of cancer cell lines of different origins and such overexpression promotes carcinogenic transformation indicating that this protein possesses oncogenic properties. [20] WRAP53β is overexpressed in primary nasopharyngeal carcinoma, [21] esophageal squamous cell carcinoma [22] and rectal cancer. [23] Moreover, knockdown of WRAP53β in cancer cells reduced the size of the tumors formed when these are grafted into mice [21] and triggers mitochondrial-dependent apoptosis in cancer cells. [20]
In contrary, inactivating mutations in both alleles of WRAP53β causes dyskeratosis congenita, indicating that this protein acts as tumor suppressor, rather than an oncogene. Loss of nuclear WRAP53β is also correlated with shortened survival and resistance to radiotherapy in patients with head and neck cancer. [24] With its complex roles in a number of cellular processes, WRAP53β may act as a tumor suppressor under certain conditions and as an oncogene in under others.
Single nucleotide polymorphisms (SNPs) in the WRAP53 gene have been linked to an increased risk for breast and ovarian cancer. [25] [26] [27] One of these SNPs also associate with defective DNA repair and hematotoxicity in workers exposed to benzene. [28]
The WRAP53 gene was first identified by Marianne Farnebo (maiden name Hammarsund) at Karolinska Institutet in 2006. In 2009 the WRAP53β (alias TCAB1, WDR79 and WRAP53) protein was described by Steven Artandi (Stanford University), Joan Steitz (Yale University) and Marianne Farnebo (Karolinska Institutet) independently.
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 eukaryotes. Telomeres protect the end of the chromosome from DNA damage or from fusion with neighbouring chromosomes. The fruit fly Drosophila melanogaster lacks telomerase, but instead uses retrotransposons to maintain telomeres.
Cajal bodies (CBs) also coiled bodies, are spherical nuclear bodies of 0.3–1.0 µm in diameter found in the nucleus of proliferative cells like embryonic cells and tumor cells, or metabolically active cells like neurons. CBs are membrane-less organelles and largely consist of proteins and RNA. They were first reported by Santiago Ramón y Cajal in 1903, who called them nucleolar accessory bodies due to their association with the nucleoli in neuronal cells. They were rediscovered with the use of the electron microscope (EM) and named coiled bodies, according to their appearance as coiled threads on EM images, and later renamed after their discoverer. Research on CBs was accelerated after discovery and cloning of the marker protein p80/Coilin. CBs have been implicated in RNA-related metabolic processes such as the biogenesis, maturation and recycling of snRNPs, histone mRNA processing and telomere maintenance. CBs assemble RNA which is used by telomerase to add nucleotides to the ends of telomeres.
Dyskeratosis congenita (DKC), also known as Zinsser-Engman-Cole syndrome, is a rare progressive congenital disorder with a highly variable phenotype. The entity was classically defined by the triad of abnormal skin pigmentation, nail dystrophy, and leukoplakia of the oral mucosa, and MDS/AML, but these components do not always occur. DKC is characterized by short telomeres. Some of the manifestations resemble premature ageing and cognitive impairment can be a feature. The disease initially mainly affects the skin, but a major consequence is progressive bone marrow failure which occurs in over 80%, causing early mortality.
Small nuclear RNA (snRNA) is a class of small RNA molecules that are found within the splicing speckles and Cajal bodies of the cell nucleus in eukaryotic cells. The length of an average snRNA is approximately 150 nucleotides. They are transcribed by either RNA polymerase II or RNA polymerase III. Their primary function is in the processing of pre-messenger RNA (hnRNA) in the nucleus. They have also been shown to aid in the regulation of transcription factors or RNA polymerase II, and maintaining the telomeres.
In molecular biology, small nucleolar RNAs (snoRNAs) are a class of small RNA molecules that primarily guide chemical modifications of other RNAs, mainly ribosomal RNAs, transfer RNAs and small nuclear RNAs. There are two main classes of snoRNA, the C/D box snoRNAs, which are associated with methylation, and the H/ACA box snoRNAs, which are associated with pseudouridylation. SnoRNAs are commonly referred to as guide RNAs but should not be confused with the guide RNAs that direct RNA editing in trypanosomes or the guide RNAs (gRNAs) used by Cas9 for CRISPR gene editing.
Coilin is a protein that in humans is encoded by the COIL gene. Coilin got its name from the coiled shape of the Cajal bodies in which it is found. It was first identified using human autoimmune serum.
Heterogeneous nuclear ribonucleoproteins (hnRNPs) are complexes of RNA and protein present in the cell nucleus during gene transcription and subsequent post-transcriptional modification 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. Since most mature RNA is exported from the nucleus relatively quickly, most RNA-binding protein in the nucleus exist as heterogeneous ribonucleoprotein particles. After splicing has occurred, the proteins remain bound to spliced introns and target them for degradation.
Survival of motor neuron or survival motor neuron (SMN) is a protein that in humans is encoded by the SMN1 and SMN2 genes.
Telomerase reverse transcriptase is a catalytic subunit of the enzyme telomerase, which, together with the telomerase RNA component (TERC), comprises the most important unit of the telomerase complex.
Small Cajal body-specific RNAs (scaRNAs) are a class of small nucleolar RNAs (snoRNAs) that specifically localise to the Cajal body, a nuclear organelle involved in the biogenesis of small nuclear ribonucleoproteins. ScaRNAs guide the modification of RNA polymerase II transcribed spliceosomal RNAs U1, U2, U4, U5 and U12.
Survival of motor neuron 1 (SMN1), also known as component of gems 1 or GEMIN1, is a gene that encodes the SMN protein in humans.
Telomerase RNA component, also known as TR, TER or TERC, is an ncRNA found in eukaryotes that is a component of telomerase, the enzyme used to extend telomeres. TERC serves as a template for telomere replication by telomerase. Telomerase RNAs differ greatly in sequence and structure between vertebrates, ciliates and yeasts, but they share a 5' pseudoknot structure close to the template sequence. The vertebrate telomerase RNAs have a 3' H/ACA snoRNA-like domain.
H/ACA ribonucleoprotein complex subunit 4 is a protein that in humans is encoded by the gene DKC1.
Poly(A)-specific ribonuclease (PARN), also known as polyadenylate-specific ribonuclease or deadenylating nuclease (DAN), is an enzyme that in humans is encoded by the PARN gene.
Probable ATP-dependent RNA helicase DDX20, also known as DEAD-box helicase 20 and gem-associated protein 3 (GEMIN3), is an enzyme that in humans is encoded by the DDX20 gene.
Telomerase protein component 1 is an enzyme that in humans is encoded by the TEP1 gene.
Survival of motor neuron 2 (SMN2) is a gene that encodes the SMN protein in humans.
Telomeric repeat–containing RNA (TERRA) is a long non-coding RNA transcribed from telomeres - repetitive nucleotide regions found on the ends of chromosomes that function to protect DNA from deterioration or fusion with neighboring chromosomes. TERRA has been shown to be ubiquitously expressed in almost all cell types containing linear chromosomes - including humans, mice, and yeasts. While the exact function of TERRA is still an active area of research, it is generally believed to play a role in regulating telomerase activity as well as maintaining the heterochromatic state at the ends of chromosomes. TERRA interaction with other associated telomeric proteins has also been shown to help regulate telomere integrity in a length-dependent manner.
Ribosomopathies are diseases caused by abnormalities in the structure or function of ribosomal component proteins or rRNA genes, or other genes whose products are involved in ribosome biogenesis.
Hoyeraal–Hreidasson syndrome is a very rare multisystem X-linked recessive disorder characterized by excessively short telomeres and is considered a severe form of dyskeratosis congenita. Being an X-linked disorder, Hoyeraal–Hreidasson syndrome primarily affects males. Patients typically present in early childhood with cerebellar hypoplasia, immunodeficiency, progressive bone marrow failure, and intrauterine growth restriction. The primary cause of death in Hoyeraal–Hreidasson syndrome is bone marrow failure, but mortality from cancer and pulmonary fibrosis is also significant.
