TRAMP complex

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TRAMP complex (Trf4/Air2/Mtr4p Polyadenylation complex) is a multiprotein, heterotrimeric complex having distributive polyadenylation activity and identifies wide varieties of RNAs produced by polymerases. It was originally discovered in Saccharomycescerevisiae by LaCava et al., Vanacova et al. and Wyers et al. in 2005. [1]

Contents

The TRAMP complex consists of RNA helicase (Mtr4/Dob1), a poly(A) polymerase (either Trf4 or Trf5) and a zinc knuckle protein (either Air1 or Air2).The interaction between the exosomes (Rrp6p/Rrp47p) and Mtr4p of TRAMP complex helps in RNA surveillance and degradation of abnormal RNAs TRAMP.png
The TRAMP complex consists of RNA helicase (Mtr4/Dob1), a poly(A) polymerase (either Trf4 or Trf5) and a zinc knuckle protein (either Air1 or Air2).The interaction between the exosomes (Rrp6p/Rrp47p) and Mtr4p of TRAMP complex helps in RNA surveillance and degradation of abnormal RNAs

It interacts with the exosome complex in the nucleus of eukaryotic cells and is involved in the 3' end processing and degradation of ribosomal RNA and snoRNAs. [1] [2] The TRAMP complex trims the poly(A) tails of RNAs destined for Rrp6 and the core exosome down to 4-5 adenosines assisting in transcript recognition and exosome complex activation. [1] [3] The substrate specificity of exosomes is improved in the presence of TRAMP complex as it acts as a crucial cofactor and helps in maintaining various activities. [4]

In this way, TRAMP plays a critical role in ridding the cell of noncoding transcripts generated through pervasive RNA polymerase II transcription, as well as functioning in the biogenesis and turnover of functional coding and noncoding RNAs. [5]

TRAMP complex also affects various other RNA processes either directly or indirectly. It is involved in RNA export, Splicing, hetero-chromatic gene silencing and helps in maintaining stability of genome. [6]

Components

Non-Canonical Poly(A) Polymerases

Pol(A) Polymerases showed various genetic interactions with DNA Topoisomerases Top1p and hence they were called topoisomerase-related function Trf4p and Trf5p [7] [8] due to this interaction with DNA it has an important part in genomic stability. [9] In the cell Trf4p is in higher concentration as compared to Trf5p and also has a stronger effect on the phenotype. [10] Trf4p is present throughout the nucleus while Trf5p is mainly found mainly in nucleolus. The Trf4p structure consists of a central domain and a catalytic domain which is similar to the structure of canonical polymerases. [11]

The non-canonical Poly(A) polymerases (Trf4p or Trf5p) of the TRAMP complex which belong to the Cid1 family do not contain RNA recognition motif (RRM) therefore additional proteins like Air1/Air2 are required by the non-canonical polymerases for polyadenylation. [12]

Zinc knuckle proteins

The zinc knuckle proteins Air1p/Air2p (Arginine methyltransferase-interacting RING-finger protein) are mainly involved in the binding of RNAs. [13] There are five CCHC (C stands for Cysteine and H stands for Histidine) zinc knuckle motifs which are present in between the C and N terminals.

In Air2p proteins, the fourth and fifth zinc knuckle have different roles. The fourth zinc knuckle have a role in RNA binding while the fifth knuckle is important for protein-protein interactions. [14] Air2p interacts with the central domain of Trf4p and polyadenylation activity of Trf4p is dependent on this interaction as deletion or mutation of the knuckles hinders the polyadenylation activity. [14] Air1p is responsible for inhibiting methylation of Npl3p (a protein which is responsible mRNA export). Air1p/Air2p also direct abnormal mRNPs to TRAMP pathway and bring about their degradation. [15]

Ski2 like helicase Mtr4p

The Ski2 like helicase Mtr4p was discovered during the screening of heat resistant mutants that gather Poly(A) RNA in the nucleus and is mainly involved in unwinding activity. Mtr4p (also called as Dob1p) is an SF2 helicase and belongs to DExH-box RNA helicases family consisting of two RecA like domains. [16] It also consists of WH domain (Winged Helix domain), an Arch domain (also called as stalk and KOW domain [Kyprides, Ouzounis, Woese domain]) and helical bundle domain. [16] The packing of the WH and helical bundle domains on surface of the helicase core results in the formation of a channel for ssRNA. [16]

Mtr4p requires ATP or dATP hydrolysis for RNA duplex unwinding mediated by Q-motif. A single-stranded region 3' to the paired region is also essential for the unwinding activity of Mtr4p. Through direct contact with various components of exosome, Mtr4p helps in proper addition of RNA substrates of TRAMP complex to nuclear exosome. [17]

Difference between canonical and non-canonical polymerases

The difference between non-canonical and canonical Poly(A) Polymerases is that canonical polymerases help in maintaining mRNAs and its activity is regulated by a specific sequence in the mRNA [18] while polyadenylation of non-canonical polymerases uses a different regulated sequence in the RNA and specifies RNAs for degeneration or processing. [13] Canonical polymerases belong to DNA polymerase β superfamily whereas non-canonical polymerases belong to Cid1 family, another main difference is the length of the poly(A) tail; canonical polymerases can add many adenylates thus the RNA produced has longer poly(A) tails while non-canonical polymerases on the other hand can produce RNAs with shorter length of poly(A) tails as they can add only few adenylates. [19]

Interaction with 3’->5’ exonuclease complex exosome

The TRAMP complex brings about degradation or processing of various RNAs with the help of 3’->5’ exonuclease complex called the exosome. A hexameric ring of RNase PH domain proteins, Rrp41p, Rrp42p, Rrp43p, Rrp45p, Rrp46p and Mtr3p comprises the exosome of S. cerevisiae. [20] The exosome can bring about RNA degradation more efficiently in the presence of Rrp6p with the help of TRAMP complex invitro. Also, RNA degradation is enhanced in the presence of various exosome cofactors which are recruited co-transcriptionally. [21]

The Ski complex consisting of Ski2p, Ski3p, Ski8p is required by cytoplasmic exosome for all mRNA degradation pathways. [22] The cytoplasmic exosome along with the Ski7p protein attaches to various abnormal ribosomes and mRNAs and brings about their degradation. [20]

Inter-relation between components

All the components of the TRAMP complex are inter-related to each other. For the activity of Poly(A) polymerases likeTrf4p/Trf5p, zinc knuckle proteins are essential. In similar way RNA degradation brought about by exosomes is stimulated by unwinding activity of Ski2 like helicases and Mtr4p which acts as a cofactor. The unwinding activity of Mtr4p is improved by the Trf4p/Air2p in the TRAMP complex. [13] Mtr4p also has an important role in maintaining and controlling the length of Poly(A) tails. But destruction or absence of Mtr4p results in hyperadenylation and hinders the length of Poly(A) tails.

A complex formed between Trf5p, Air1p and Mtr4p is called as TRAMP5 complex. [15] In S. cerevisiae there are two types of TRAMP complexes depending on the presence of polymerases. If Trf4p is present, then the complex is called as TRAMP4 and if Trf5p is present then It is called as TRAMP5. [23]

RNA substrates

RNAs produced by all three polymerases (Pol I, II, III) act as substrates for TRAMP complex. TRAMP complex is involved in processing and surveillance of various RNAs and degrade abnormal RNAs. Different type of RNA substrates include ribosomal RNAs (rRNAs), small nucleolar RNAs (snoRNAs), transfer RNAs (tRNAs), small nuclear RNAs (snRNAs), Long transcripts of RNA polymerase II (Pol II) etc. But the mechanism by which TRAMP complex identifies various substrates is unknown.

The TRAMP complex works more efficiently in RNA processing by engaging Exosome complex exonuclease RrP6 wherein Nab3(RNA binding protein) plays a crucial role. [15] [23]

Role in maintaining chromatin

Post-transcriptional modifications due to various enzymes like methyltransferase Hmt1p (Rmt1p) may have an indirect effect on chromatin maintenance. The chromatin structures are affected when RNA substrates of TRAMP complex are transcribed across the genome. Various TRAMP components interact physically and genetically with various proteins and bring about changes in chromatin and DNA metabolism. [1]

Conservation of TRAMP-mediated processes

Components of the TRAMP complex in Saccharomyces cerevisiae are conserved in other organisms ranging from yeast to mammals. The TRAMP complex components of Schizosaccharomyces pombe including Cid14p, Air1p, and Mtr4p are functionally similar to the components of TRAMP complex in S. cerevisiae. [24]

In humans

The TRAMP complex in humans consists of various components including the helicase hMtr4p, a non-canonical poly(A) polymerase hPAPD (PAP-associated domain-containing) 5 or hPAPD7, and a Zinc knuckle protein hZCCHC7, RNA binding protein hRbm7p. [25]

Related Research Articles

Messenger RNA RNA that is read by the ribosome to produce a protein

In molecular biology, messenger ribonucleic acid (mRNA) is a single-stranded molecule of RNA that corresponds to the genetic sequence of a gene, and is read by a ribosome in the process of synthesizing a protein.

In genetics, a transcription terminator is a section of nucleic acid sequence that marks the end of a gene or operon in genomic DNA during transcription. This sequence mediates transcriptional termination by providing signals in the newly synthesized transcript RNA that trigger processes which release the transcript RNA from the transcriptional complex. These processes include the direct interaction of the mRNA secondary structure with the complex and/or the indirect activities of recruited termination factors. Release of the transcriptional complex frees RNA polymerase and related transcriptional machinery to begin transcription of new mRNAs.

Polyadenylation is the addition of a poly(A) tail to an RNA transcript, typically a messenger RNA (mRNA). The poly(A) tail consists of multiple adenosine monophosphates; in other words, it is a stretch of RNA that has only adenine bases. In eukaryotes, polyadenylation is part of the process that produces mature mRNA for translation. In many bacteria, the poly(A) tail promotes degradation of the mRNA. It, therefore, forms part of the larger process of gene expression.

In molecular biology, the five-prime cap is a specially altered nucleotide on the 5′ end of some primary transcripts such as precursor messenger RNA. This process, known as mRNA capping, is highly regulated and vital in the creation of stable and mature messenger RNA able to undergo translation during protein synthesis. Mitochondrial mRNA and chloroplastic mRNA are not capped.

Exonuclease Class of enzymes; type of nuclease

Exonucleases are enzymes that work by cleaving nucleotides one at a time from the end (exo) of a polynucleotide chain. A hydrolyzing reaction that breaks phosphodiester bonds at either the 3′ or the 5′ end occurs. Its close relative is the endonuclease, which cleaves phosphodiester bonds in the middle (endo) of a polynucleotide chain. Eukaryotes and prokaryotes have three types of exonucleases involved in the normal turnover of mRNA: 5′ to 3′ exonuclease (Xrn1), which is a dependent decapping protein; 3′ to 5′ exonuclease, an independent protein; and poly(A)-specific 3′ to 5′ exonuclease.

RNA polymerase II Protein complex that transcribes DNA

RNA polymerase II is a multiprotein complex that transcribes DNA into precursors of messenger RNA (mRNA) and most small nuclear RNA (snRNA) and microRNA. It is one of the three RNAP enzymes found in the nucleus of eukaryotic cells. A 550 kDa complex of 12 subunits, RNAP II is the most studied type of RNA polymerase. A wide range of transcription factors are required for it to bind to upstream gene promoters and begin transcription.

Post-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, functional RNA molecule that can then leave the nucleus and perform any of a variety of different functions in the cell. There are many types of post-transcriptional modifications achieved through a diverse class of molecular mechanisms.

Ribosome biogenesis Cellular process

Ribosome biogenesis is the process of making ribosomes. In prokaryotes, this process takes place in the cytoplasm with the transcription of many ribosome gene operons. In eukaryotes, it takes place both in the cytoplasm and in the nucleolus. It involves the coordinated function of over 200 proteins in the synthesis and processing of the three prokaryotic or four eukaryotic rRNAs, as well as assembly of those rRNAs with the ribosomal proteins. Most of the ribosomal proteins fall into various energy-consuming enzyme families including ATP-dependent RNA helicases, AAA-ATPases, GTPases, and kinases. About 60% of a cell's energy is spent on ribosome production and maintenance.

Exosome complex Protein complex that degrades RNA

The exosome complex is a multi-protein intracellular complex capable of degrading various types of RNA molecules. Exosome complexes are found in both eukaryotic cells and archaea, while in bacteria a simpler complex called the degradosome carries out similar functions.

Polynucleotide phosphorylase Class of enzymes

Polynucleotide Phosphorylase (PNPase) is a bifunctional enzyme with a phosphorolytic 3' to 5' exoribonuclease activity and a 3'-terminal oligonucleotide polymerase activity. That is, it dismantles the RNA chain starting at the 3' end and working toward the 5' end. It also synthesizes long, highly heteropolymeric tails in vivo. It accounts for all of the observed residual polyadenylation in strains of Escherichia coli missing the normal polyadenylation enzyme. Discovered by Marianne Grunberg-Manago working in Severo Ochoa's lab in 1955, the RNA-polymerization activity of PNPase was initially believed to be responsible for DNA-dependent synthesis of messenger RNA, a notion that got disproved by the late 1950s.

Non-stop decay

Non-stop decay (NSD) is a cellular mechanism of mRNA surveillance to detect mRNA molecules lacking a stop codon and prevent these mRNAs from translation. The non-stop decay pathway releases ribosomes that have reached the far 3' end of an mRNA and guides the mRNA to the exosome complex, or to RNase R in bacteria for selective degradation. In contrast to Nonsense-mediated decay (NMD), polypeptides do not release from the ribosome, and thus, NSD seems to involve mRNA decay factors distinct from NMD.

The Ski complex is a multi-protein complex involved in the 3' end degradation of messenger RNAs in yeast.

The degradosome is a multiprotein complex present in most bacteria that is involved in the processing of ribosomal RNA and the degradation of messenger RNA and is regulated by Non-coding RNA. It contains the proteins RNA helicase B, RNase E and Polynucleotide phosphorylase.

In enzymology, a polyphosphate kinase, or polyphosphate polymerase, is an enzyme that catalyzes the formation of polyphosphate from ATP, with chain lengths of up to a thousand or more orthophosphate moieties.

Exosome component 2

Exosome component 2, also known as EXOSC2, is a protein which in humans is encoded by the EXOSC2 gene.

SKIV2L

Helicase SKI2W is an enzyme that in humans is encoded by the SKIV2L gene. This enzyme is a human homologue of yeast SKI2, which may be involved in antiviral activity by blocking translation of poly(A) deficient mRNAs. The SKIV2L gene is located in the class III region of the major histocompatibility complex.

SKIV2L2

Superkiller viralicidic activity 2-like 2 is a protein that in humans is encoded by the SKIV2L2 gene.

mRNA surveillance mechanisms are pathways utilized by organisms to ensure fidelity and quality of messenger RNA (mRNA) molecules. There are a number of surveillance mechanisms present within cells. These mechanisms function at various steps of the mRNA biogenesis pathway to detect and degrade transcripts that have not properly been processed.

Cryptic unstable transcripts (CUTs) are a subset of non-coding RNAs (ncRNAs) that are produced from intergenic and intragenic regions. CUTs were first observed in S. cerevisiae yeast models and are found in most eukaryotes. Some basic characteristics of CUTs include a length of around 200–800 base pairs, a 5' cap, poly-adenylated tail, and rapid degradation due to the combined activity of poly-adenylating polymerases and exosome complexes. CUT transcription occurs through RNA Polymerase II and initiates from nucleosome-depleted regions, often in an antisense orientation. To date, CUTs have a relatively uncharacterized function but have been implicated in a number of putative gene regulation and silencing pathways. Thousands of loci leading to the generation of CUTs have been described in the yeast genome. Additionally, stable uncharacterized transcripts, or SUTs, have also been detected in cells and bear many similarities to CUTs but are not degraded through the same pathways.

RRM3

RRM3 is a gene that encodes a 5′-to-3′ DNA helicase known affect multiple cellular replication and repair processes and is most commonly studied in Saccharomyces cerevisiae. RRM3 formally stands for Ribosomal DNArecombination mutation 3. The gene codes for nuclear protein Rrm3p, which is 723 amino acids in length, and is part of a Pif1p DNA helicase sub-family that is conserved from yeasts to humans. RRM3 and its encoded protein have been shown to be vital for cellular replication, specifically associating with replication forks genome-wide. RRM3 is located on chromosome 8 in yeast cells and codes for 723 amino acids producing a protein that weighs 81,581 Da.

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