2009 Group 9 Project

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The Nucleus

The nucleus is a double membrane organelle arranged concentrically and found in the majority of eukaryotic cells. Particular cells such as mature red blood cells and xylem may have lost their nucleus during their progression of growth. The nucleus is predominantly seen as spherical or oval shaped and appear in a variety of sizes. A typical mammalian cell nucleus ranges between 10-15µm and maintains genetic information in a central region. The nucleus is a prominent structure that denotes the difference between eukaryotic cells and prokaryotic cells by its presence. [1]

The double membrane of the nucleus is termed the ‘nuclear envelope’ that acts to create a compartment segregated from the cytoplasm of the cell. This compartment is called the ‘nuclear compartment’ and contains various internal structures including chromatin, chromosomes, deoxyribonucleic acid and the nucleolus. The double membrane comprises of an external membrane and internal membrane. The external membrane may be continuous with the endoplasmic reticulum located adjacent to the nucleus. Whilst, the internal membrane provides structural support through the presence of a cytoskeleton comprised of fibrous protein.[2]

The function of the nucleus involves monitoring and coordinating activities undertaken throughout the cell. It includes the initiation of gene expression through modification of messenger ribonucleic acid (mRNA) and monitoring various stages by selectively permitting proteins to enter the nuclear compartment.

Image of a Nucleus

History of nuclear membrane development

Prokaryotic cells have the presence of deoxyribose nucleic acid (DNA) floating within the cytoplasm throughout its history and today. The development of nucleus involves the invagination of the plasma membrane from prehistoric prokaryotic cells. Evolution has caused the infolding of the plasma membrane causing extracellular fluid and plasma membrane constituents to surrounding the DNA. Subsequently, the region of plasma membrane introversion separated from the external environment creating a partition. The separated membrane structure collapsed and fused together creating a bi-layered lipid membrane that is called the ‘nuclear envelope’ today. Collectively, all membranous parts of a cell constitute towards an aggregate called the ‘endomembranous system’.[3]

Nuclear Envelope

The nuclear envelope is a distinct structure that maintains a unique biochemical compartment selectively away from the cytosol. The nuclear envelope aims to control the movement of large and small molecules through selective channels and pathways. Amongst the nuclear membrane, there are structures located intermittently along the nuclear envelope with sole purpose of controlling flow called nuclear pore complexes. The nuclear envelope is comprised of two constituents namely, the inner membrane and outer membrane. These two membranes are structured similarly with minor differences and may have an intervening space called the perinuclear space. [4][5]

The outer membrane is primarily comprised of a bi-layered phospholipid coat with proteins, cholesterol, lipids and possibility of ribosomes dispersed amongst its fluid structure. The outer membrane extends away from the nucleus to form the endoplasmic reticulum that is designated for protein synthesis. Due to this phenomenon, it causes the peri-nuclear space of the nucleus to become continuous with the convoluted tubules of the endoplasmic reticulum.

The inner membrane is constructed with a variety of different proteins in the bilayered membrane. It also has a nuclear cytoskeleton attached at irregular intervals, which has a sole purpose of maintaining the fundamental structure of the nucleus.

The nuclear lamina is an additional opaque layer located underlying the inner face of the inner membrane. It is relative thin at approximately 20µm and is composed of proteins called lamins. The nuclear lamina provides a molecular interface interlinking the chromatin of the nucleus and the nuclear envelope. It acts to provide a framework for structural support and permits the presence of anchoring sites for chromatin domains.[6][7]

Lamins are polypeptides belonging to the V-Intermediate Filament protein family. Lamins are found in a rod-shaped form with a main coiled region associated with nitrogen and carbon terminal domains. Mammalian cells comprise of lamins that are encoded according to genes: LMNA, LMNB1 and LMNB2. The LMNA gene allows encoding and the production of lamins A and C. The LMNB1 and LMNB2 genes trigger protein formation of lamins B1 and B2 respectively. The presence of lamin B1 contributes to the majority of the lamin species within the lamina. The composition of the nuclear lamina involves mainly nuclear lamins and a large number of lamin variants. The nuclear lamina acts as an intermediate linkage between the chromatin and the nuclear envelope of a cell. It allows interactions between proteins of nucleosomes within the chromatin and the nuclear envelope. The structure of the nuclear lamina provides a framework for structural support and mechanical stability by anchoring at sites of chromatin domains and the nuclear envelope. [8][9]

Image of Nuclear Envelope

The Nuclear Pore Complex

Nuclear pore complexes are dispersed randomly across the nuclear envelope creating a passageway through the nuclear envelope and connecting the cytoplasm to the nucleoplasm. It is a fluid filled chamber maintaining an essential physiological task in cell survival. The size of a nuclear pore may extend up to 120nm that is 30 times greater than a ribosome. Nuclear Pore Complexes are built on a central framework that is vertically 8-fold symmetrical through the nuclear envelope called a ‘‘spoke complex’’. It is integral in ensuring that the entire structure is embedded into the nuclear envelope. The cytoplasmic and nuclear side of the ‘spoke complex’ has subunit components attached to it called the ‘’cytoplasmic ring’’ and ‘’nuclear ring’’ respectively.[10][11][12]

The aggregate structure of the nuclear pore complex involves the spoke complex along with the cytoplasmic and nuclear rings. The cytoplasmic ring has eight filaments called ‘’cytoplasmic filaments’’ attached to its outermost regions extending into the cytoplasm. The nuclear ring appears in an arrangement over the nuclear pore extending into nucleoplasm distally. It has additional filaments creating a ‘’nuclear basket’’ that is structured similar to a basketball net. Prash, brke The nuclear pore complex has the presence of a large central channel and multiple peripheral channels. The central channel permits molecules up to 26nm to pass through only with a nuclear import or export signal (otherwise called ‘’nuclear localization signal’’). Thus despite the expansive size of the central channel, ribosomes and organelle constituents cannot pass through into the nucleus. Additionally, there are peripheral channels with the sole purpose to enable free bidirectional exchange of small molecules with a size less than 10 nm.[13][14][15]

The movement of proteins through the nuclear pore from the cytoplasm requires binding to a unique cytosolic protein as an import signal called a ‘’nuclear transport receptor.’’ The protein-receptor complex will need to pass through a diaphragm structure within the central channel of the nuclear pore. The diaphragm is designed to maintaining a concentration gradient of the protein by implementing facilitated transport. Subsequent to entry into the nucleoplasm, the nuclear transport receptor detaches from the protein and returns to the cytoplasm by flowing back through the nuclear pore to the cytoplasm.[16][17]

Alongside the foundation of the nuclear pore complex, there are filamentous structures that extend outwards into the cytoplasm and nucleoplasm that are ‘’cytoplasmic filaments’’ and ‘’long filaments’’. The cytoplasmic filaments adhere to the cytoplasmic ring acting as docking sites for proteins signaled to be transferred into the nucleus. On the furthest point of the nuclear ring, eight ‘’long filaments’’ of lengths 50-100nm are interconnected at their distal ends creating a ring called a ‘’nuclear basket’’. This particular region is subject to docking of translocating molecules and permits expansion to accommodate for molecules of greater sizes.[18][19][20][21]

The composition of the nuclear pore complex involves 50-100 varieties of protein subunits codenamed ‘’nucleoporins’’. These proteins are accompanied by integral membrane proteins due to its side attachments to anchor the nuclear pore into the nuclear envelope. The remainder of nuclear pore constituents are soluble proteins with a repetitive sequence motif GLFG and/or XFXFG. In this instance, G stands for glycine, F for phenylalanine, L for leucine and X for small polar molecule. The nature of these extra species of nucleoporins is unknown although are suspected to aid import and export receptors for nucleocytoplasmic transport.[22][23][24]

Image of Nuclear Pore Complex


Nucleolus

The nucleolus is one of the most prominent structures in the nucleus. In various cases, depending on the reproductive stage of the cell, there may be more than one nucleoli present. This is the site of ribosomal RNA (rRNA) transcription, where the rRNAs are synthesized, processed and assembled with ribosomal proteins to form ribosomes. This cycle occurs and repeats during late telophase, through interphase but breaks down when the cell proceeds to the mitosis stage. [25]

Chromosome

Chromosomes are discovered in a pairs with half derived from the paternal parent and the other half from the maternal parent. Each constituent of a chromosome pair is individually called a homolog. A chromosome is a linear DNA molecule filled with proteins that is folded repeated. [26][27]

Somatic cells have the tendency to contain diploid (2n) chromosomes that are created through the fusion of gametes from haploid (n) chromosomes. Human cells are comprised of 23 pairs of chromosomes that are 22 pairs of autosomes and 1 pair of sex chromosome. Chromosomes contain two arms within each strand; one being a shorter ‘’p’’ arm and a longer ‘’q’’ arm. The human genomes contains about 3.4 × 10^9 bp with a total of 30 000 genes that is condensed into chromosomes. Chromosomes are viewable mainly during mitosis with a length ranging from 3-7µm due to packing and unpacking. [28][29]

Chromosomes during interphase are maintained into compartments within the nucleus called ‘’chromosomal territories’’. Different chromosomes are positioned in accordance to the level of gene content and stage within the chromatin replication process. Chromosomes that are considered gene-poor and activate in late stages of chromatin replication are preferentially found closer to nuclear envelope. In opposition, gene-rich chromosomes required for early stages of chromatin replication are located closer to centre of nucleus. [30][31]

Image of Chromosomal Territories

The pair of sex chromosomes located in the DNA is the main determinant of gender. Females inherit one X chromosomes from the mother and another X chromosome from the father. On the other hand, males inherit one X chromosome from the mother and a Y chromosome derived from father. [32][33]

Chromosomes are structured in a complex fashion with the subunits:

  • heterochromatin
  • euchromatin
  • centrosomes
  • telomeres


Image of a Chromosome


Banding of chromosomes

Giemsa staining is a revolutionary banding technique that allows individual chromosomes to be viewed through exposure of chromosomes to typsin. It produces two distinct colours either Giemsa dark (G) or Giemsa light (R) bands that discriminates against higher order structures in chromosomes required for replication during transcription.

The light G bands (R) comprise of a high degree of guanine and cytosine with gene-rich concentrations for maintenance and housekeeping. Alongside the gene composition, short intersperse repetitive DNA sequences (SINE) repeats are also unique to these regions. On the other hand, dark G bands consists of a high proportion of adenine and thymine that are gene-poor although selectively hold tissue-specific genes. The foundation of these regions involves long interspersed repetitive DNA sequence (LINE) repeats. G and R bands are found localised in different domains with G bands tending to be located nearer to the nuclear envelope and R bands being centralised in nucleus.[34]


Deoxyribonucleic Acid (DNA)

Deoxyribonucleic acid is the functional unit of carrying genetic information of an organism. The physical structure has two complementary chains of nucleotides called ‘’DNA strands’’ arranged in a spiral anti-parallel fashion. The union of the strands is maintained by hydrogen bonds located regularly on the complimentary chains. The deoxyribonucleic acid (DNA) chains extends to a length of 2 metres long and are 10µm in diameter with multiple convolutions, loops and coils through proteins. DNA is composed of 23 pairs of ‘’nuclear chromosomes’’ numbered from largest to smallest.[35][36]

The nucleotides are found with a 5-carbon sugar called ribose connected to a phosphate group and a nitrogen base. The nitrogen bases called nucleotides may be adenine (A), cytosine (C), guanine (G) or thymine (T). The nitrogen base acts as a substituent group attached to the sugar backbone of a DNA strand. The DNA backbone involves the ribose and phosphate groups alternating in a polypeptide fashion i.e. –(sugar-phosphate-sugar-phosphate)n–.[37][38]

The sugar-phosphate backbone are located at the periphery with the nitrogen bases act as an intermediate between the two strands with hydrogen bond linkages. It creates a ladder-like structure with each rung comprised of two complimentary nucleotides being called ‘’base pairs’’. It is designed in this particular manner to allow a regular structure with nucleotides being equidistant along the entire double helix.

The DNA double helix interweaves with one full helical turn constructed every ten bases with the anti-parallel complementation of DNA strands oriented opposite each other. It occurs through the equivalent lengths between DNA strands arranged with the pairing of thymine with adenine and guanine with cytosine. This is possible due to the size of the nucleotides with a purine nucleotide binding with a pyrimidine nucleotide. Each nucleotide may be classified as either a purine or pyrimidine dependent upon whether they are a double ring base or single ring base respectively. In DNA, adenine and guanine are purine bases whilst cytosine and thymine are pyrimidine bases.

Image of DNA

The degree of DNA being twisted is called DNA supercoiling dependent upon the activity of enzymes called topoisomerases. These enzymes attempt to promote ‘’negative supercoiling’’ causing the DNA double helix to relax and become less twisted. Alternatively, inactivity increases twisting of DNA called ‘’positive supercoiling’’ bringing the base pairs closer together.[39][40]

Deoxyribonucleic acid can be divided into a set of linear chromosomes called a ‘’genome.’’ A genome constitutes to the total number of genetic material in a cell with human cells containing 3 billion base pairs configured into 46 chromosomes. Heredity information is coded onto DNA strands called ‘’genes’’ potentially producing a biological message through transcription and translation. [41][42]


Heterochromatin and Euchromatin

Chromosomes are not evident during an interphase nucleus although it composes specific parts of chromatin that can be detected by staining. The staining of the fragments allows identification of ‘’heterochromatin’’ and ‘’euchromatin’’. Heterochromatin are chromosomal partitions that can be stained and traced throughout a cell cycle. Euchromatin differs as it becomes invisible during telophase and interphase. Staining is possible as heterochromatin has few activated genes and tends to contain deoxyribose nucleic acid (DNA) sequences. [43]


Centromere

Centromeres are chromosomal substructures that maintain segregation of chromosomes when producing daughter cells by meiosis and mitosis. Centromeres may be found singularly on the majority of eukaryotic chromosomes attaching sister chromatids. It is involved in key cell cycle processes including spindle microtubule attachment, mitotic checkpoint control, sister-chromatid cohesion and cytokinesis. Transmission of the centrosome remains evident at an identical chromosomal destination before and after cell division. Control of centromere structure and function is regulated through the presence of centromeric deoxyribonucleic acid (DNA) sequences rather than primary DNA sequences. The composition of a centromere involves tandem repeated satellite DNA sequences that differs slightly amongst organisms.[44][45]

Location of Centromere

In human chromosomal centromeres, α-satellite DNA is the main constituent; made of 169-172 base pair monomers in addition to specific higher-order repeat units. Each higher-order repeat may appear in variations of up to 30 diverged monomers in length and is influenced primarily by intrachromosomal processes. The aggregate structure of the α-satellite DNA involves several thousand multimer tandem repetitions. The α-satellite DNA of humans can be separated into different categories of suprachromosomal families, each with a unique set of monomeric types. Each subfamily is associated with specific regions having alternate compositions and located similarly on the chromosome.[46][47]

Image of Centromeres

Centromere-associated Proteins

The majority of centromere-associated proteins remain highly conserved that contributes towards structure and function. These centromere proteins (CNEPs) may be identified as either CENP-A, CENP-B, CENP-C, CENP-D, and CENP-E and remain part of the centromere in the cell cycle.

  • CENP-A is a histone H3 that may be found at the kinetochore plate within centromeres and binds α-satellite DNA. It is shown as an arrangement on the surface of centromeric heterochromatin that is essential for centromere construction and function.
  • CENP-B acts to help stabilize centromere development and structure.
  • CENP-E is a kinesin-like motor protein located at the kinetochore plate and belongs to a second class of centromeric proteins.

Sister chromatids are joined at centromeres by cohesion by many proteins. These proteins vary along the chromosomal arms and centromeres and activated/deactivated throughout the cell replication process.[48][49]


Telomeres

Telomeres are specialized DNA-protein complexes located on the ends or ‘caps’ of human chromosomes. The function of the telomeres involves completing constantly building and breaking down of terminal DNA and prevention of chromosomal degradation. A unique ribonucleoprotein enzyme called telomerase is necessary to regulate long term telomeric DNA production and repair. These dynamic complexes involve DNA tandem repeats of 6 base pairs, which contain clusters of guanine (G) residences on chromosomal termini. It is evident through the presence of TTAGGG in humans. Replication of telomeric DNA may occur through a variety of different ways. Telomeric DNA-binding proteins may also attach to telomeric DNA through signaling from the nucleotide sequence producing a high-order DNA.[50][51]

Telomerase is a vital ribonucleoprotein enzyme activated to attach telomeric DNA onto pre-existing telomere DNA of chromosomes. The terminal region on the linear DNA molecule involves telomeric DNA that replicates by telomerase and traditional semiconservative DNA replication enzyme machinery. It protects chromosomal material by ensuring that chromosomal DNA is essentially replicated entirely. In addition, telomerase repair broken DNA ends through mending telomeres by adding telomeric repeats onto it. Dysfunctional telomerase leads to telomere shorting and destroys the ability of cellular proliferation.[52]

Image of Telomeres on a Chromosome

Telomerase is constituted by two components: human telomere reverse transcriptase (hTERT) acting as a catalyst and human telomerase ribonucleic acid (hTR) as a RNA part. Telomerase implements the RNA component as template for reverse transcription that builds TTAGGG repeats onto chromosomal telomeres. It helps maintain and regulate telomere length thus in its absence, somatic cells may lose telomeric sequences naturally by cell division. There has also been the discovery that there is a correlation between telomere length and cellular ageing.[53]

In eukaryotic human cells, telomeric DNA comprises of up to 20 kilobases of tandemly repeated TTAGGG sequences. It involves thymine, adenine and guanine. It may be found alongside two proteins being: telomeric repeat binding factor 1 (TRBF1) and 2 (TRBF2). Coordinated expression of these proteins act upon telomeric DNA directly, subsequently, controlling telomere length.[54]

Normal somatic cell division causes telomeres to shorten by 50-200 bp due to inability for DNA to replicated particular aspects of each end. This is called the ‘’end replication problem’’ due to progressive loss of telomeric sequences.

Telomeric regions have increased genetic recombination within males and females but more greatly in men. The telomere recombination leads to different levels of exchange and imbalances of gene dosage. Meiosis requires telomeres to permit chromosome pairing acting as primary region of union and synapse of chromosomes. Hence it is important for controlling homologous chromosome pairing. A transition of telomere towards the nuclear envelope clustering in a ‘’bouquet formation’’ indicates chromosome pairing. It can lead to exchange of material between non-homologous chromosomes.[55][56]

Subtelomeric regions

Subtelomeric regions are located proximal to the human tandem repeated sequences of TTAGGG. These may also be known as telomere-associated DNA that has segments of shared homology between different chromosomes. Subtelomeric regions are generally a combination of shared repeated DNA alongside additional sequence homologies. It has the main purpose of sequencing information from various telomere regions.

There are the presence of two subdomains in telomeres that being a distal subdomain and proximal subdomain. The distal subdomain is located nearer to the TTAGGG repeat involves many short sequences with shared homologies shorter than 2 kilobases. The proximal subdomain differs with longer seqments up to 40 kilobases of shared homologies present in lesser proportion of chromosomes. The proximal and distal subdomains are intervened by many degenerate TTAGGG repeats and replication-specific sequences. It helps in the functional arrangement of telomere repeats.[57]

Unique Sequence DNA

There may be unique sequence DNA adjacent to subdomain telomeric regions further away from the end of the chromosome. It ranges in length up to 300 kilobases being the highest density of genes.[58]




Mutation and Disease

Nucleus plays a major role in a cell and contains large number of different proteins. As the result it is very susceptible for the occurrence of disease only by small number of mutations in its proteins.

One of the major structures of nucleus is nuclear envelope which consists of different types of membrane. Protein lamins as the constituent of the inner nuclear membrane contain LMNA loci which can cause several inherited disease if mutation occurs. Specifically Lamins A and C mutation can result in 4 major categories of diseases such as:

1) Striated Muscle Disease

  • Autosomal Dominant Emery-Dreifuss Muscular Distrophy

2) Partial Lipodystrophy Syndromes

  • Dunnigan-type Partial Lipodystrophy

3) Peripheral Neuropathy

  • Charcot-Marie-Tooth Disorder Type 2B1

4) ‘Premature Ageing’ Syndromes



References

Template:Reflist



2009 Group Projects

--Mark Hill 14:02, 19 March 2009 (EST) Please leave these links to all group projects at the bottom of your project page.

Group 1 Meiosis | Group 2 Cell Death - Apoptosis | Group 3 Cell Division | Group 4 Trk Receptors | Group 5 The Cell Cycle | Group 6 Golgi Apparatus | Group 7 Mitochondria | Group 8 Cell Death - Necrosis | Group 9 Nucleus |

Group 10 Cell Shape

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