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MCP 1-04 - Nuclear Structure and Function
SUNY Upstate College of Medicine Class of 2015
108
Biochemistry
Professional
09/03/2011
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Term
What are the functions of the nucleus?
 Definition
1) Protect the chromosomes from damage.
2) Repair the chromosomes when damaged.
3) Replicate the chromosomes.
4) Facilitate the expression of genetic programs through the transcription of gene sets.
5) Synthesize ribosomes.
Term
Nuclear envelope.
 Definition
The nuclear envelope is a double membrane that is contiguous with the endoplasmic reticulum.
Term
Nuclear lamina.
 Definition
A meshwork of intermediate filaments made by oligomerization of the intermediate filament proteins lamin A, B, and C. It is attached to the inner membrane of the nuclear envelope and helps to stabilize the nuclear envelope and organize chromosomes. Phosphorylation of the lamin proteins at mitosis induces disassembly of the nuclear lamina which in turn causes nuclear breakdown.
Term
What is the nuclear lamina made up of?
 Definition
Intermediate filaments.
Term
How is the nuclear lamina made?
 Definition
Made by oligomerization of the intermediate filament proteins lamin A, B, and C.
Term
Oligomerization.
 Definition
A chemical process that converts monomers to a finite degree of polymerization.
Term
Where is the nuclear lamina located? What is its function?
 Definition
It is attached to the inner membrane of the nuclear envelope and helps to stabilize the nuclear envelope and organize chromosomes.
Term
What is the role of the lamin in mitosis?
 Definition
Phosphorylation of the lamin proteins at mitosis leads to a conformational change which induces disassembly of the nuclear lamina which in turn causes nuclear breakdown.
Term
Nuclear breakdown.
 Definition

[image]

Phosphorylation of the lamin proteins at mitosis induces disassembly of the nuclear lamina which in turn causes nuclear breakdown. 
Term
What happens to the nucleus before mitosis?
 Definition
1) Transcription ceases.
2) Nucleolus dissolves.
3) Chromosomes condense.
4) Modification of the lamins causes the nuclear envelope to break down into vesicles.
Term
What happens to the nucleus after mitosis?
 Definition
1) Lamin A is dephosphorylated.
2) Nuclear envelope vesicles fuse onto de- condensing chromosomes.
3) Chromosomes fuse.
4) Transcription of rDNA repeats leads to re-formation of the nucleolus first as 10 pre-nucleolar foci.
Term
Nuclear pores.
 Definition

[image]

Proteinaceous channels through the nuclear envelope that provide conduits through which all molecules move into and out of the nucleus.

 
Term
What is the diameter of nuclear pores?
 Definition
9 nm.
Term
Proteins below what mass can diffuse through the nuclear envelope?
 Definition
Proteins below 44kDa.
Term
How do larger proteins traverse the nuclear envelope?
 Definition
Facilitated diffusion.
Term
How many nuclear pores do most cells contain?
 Definition
Between 3,000 and 4,000.
Term
What is the structure of the nuclear pores?
 Definition
~125 Mega Daltons, ~100 proteins arranged in 8-fold symmetry.
Term
What's the general mechanism of transport for both export and import from/to the nucleus?
 Definition
The process is facilitated by carrier proteins that recognize transport substrates via signals on the substrates: nuclear localization signals for import and nuclear export signals for export. The carrier binds the substrate and acts as an escort through the pore.
Term
What is the role of Ran in transport to/from the nucleus?
 Definition

The energy for transport comes from GTP hydrolysis by the G-protein Ran. Ran-GDP predominates on the cytosolic face while Ran- GTP predominates on the nuclear face. This is due to the asymmetric localization of the Ran GAP and Ran GEF respectively.

[image]
Term
Where does the energy for transport come from?
 Definition
The energy for transport comes from GTP hydrolysis by the G-protein Ran. GTP is used to establish a Ran gradient which drives nuclear transport.
Term
Does Ran-GDP predominate on the cytosolic or the nuclear face?
 Definition
The cytosolic face. (Due to the activity of Ran GAP1.)
Term
Does Ran-GTP predominate on the cytosolic or the nuclear face?
 Definition
The nuclear face. (Due to the activity of RanGEF.)
Term
Ran
 Definition
Small GTPase - binds & hydrolyzes GTP (Ran hydrolyzes GTP at a very slow rate). Ran can exist in 2 forms: Ran GTP and Ran GDP.
Term
RCG-1 (RanGEF)
 Definition
On the nuclear side (bound to chromosomes) of the lamina, takes Ran GDP and replaces GDP with GTP.
Term
Ran GAP1
 Definition
GAP = GTP activating Protein. On the cytosolic side (bound to the fibers of the nuclear pore) of the lamina, binds to Ran GTP induces it to hydrolyze GTP, resulting in Ran GDP.
Term
GTPase
 Definition
Enzyme that can bind and hydrolyze GTP.
Term
Nuclear localization signals.
 Definition
An amino acid sequence which 'tags' a protein for import into the cell nucleus by nuclear transport. Typically, this signal consists of 4-8 positively charged lysines or arginines exposed on the protein surface. This signal can appear anywhere in the primary sequence.
Term
Which amino acid(s) can act as nuclear localization signals?
 Definition
Lysine and arginine.
Term
What is the mechanism of nuclear transport (diagram)?
 Definition
[image]
Term
What is the mechanism of nuclear transport (text)?
 Definition
The nuclear localization signal (NLS) is recognized and bound by an importin which directs docking of the complex onto fibrils extending from the cytoplasmic face of the nuclear pore complex (NPC). The cargo-carrier complex is then translocated through the NPC, after which GTP-bound Ran directs dissociation of the carrier from the cargo and release of the NLS-containing protein into the nucleus.
Term
Importin.
 Definition
A type of protein that moves other protein molecules into the nucleus by binding to a specific recognition sequence, called the nuclear localization signal (NLS). Importin binds to the NLS of the protein to be imported to the nucleus and helps in the docking of the importin heterodimer-bound protein to the nuclear pore complex. The NLS-Importincomplex dissociates after binding to Ran GTP inside the nucleus.
Term
What is the Role of the RAN GTPase?
 Definition
1) Provide the energy for transport in the form of potential energy stored as a chemical gradient.
2) In conjunction with the carrier protein complex, specificy directionality of transport.
3) Catalyze release of the transport complex after transport and thus ensures irreversibility.
Term
Exportin.
 Definition
A carrier protein that works with Ran GTP to transport mRNA, tRNA, and rRNA from the nucleus. In the case of mRNA, the exportin recognizes a unique structure on the 5' end of the mRNA called the 5'-CAP.
Term
Briefly describe the process of nuclear export.
 Definition
Nuclear export roughly reverses the import process; in the nucleus, the exportin binds the cargo and Ran-GTP and diffuses through the pore to the cytoplasm, where the complex dissociates. Ran-GTP binds GAP and hydrolyzes GTP, and the resulting Ran-GDP complex is restored to the nucleus where it exchanges its bound ligand for GTP. Hence, whereas importins depend on RanGTP to dissociate from their cargo, exportins require RanGTP in order to bind to their cargo.
Term
What is unique about the export of mRNA from the nucleus from the standpoint of exportin?
 Definition
Exportin recognizes a unique structure on the 5' end of the mRNA called the 5'-CAP.
Term
Nucleolus.
 Definition
Non-membrane bound sub-compartment of the nucleus whose primary function is ribosome biogenesis.
Term
How is the nucleolus formed?
 Definition
On the rDNA repeats of 5 different autosomes with two homologues each for a total of 10 chromosomes per diploid cell.
Term
What are the three regions within the nucleolus?
 Definition
1) The fibrillar center - this region contains DNA that is not being actively transcribed.
2) The dense fibrillar component - this region contains rRNA molecules actively being synthesized.
3) A granular component - this region contains maturing ribosomal precursor particles.
Term
What is contained in the fibrillar center of the nucleolus?
 Definition
DNA that is not being actively transcribed.
Term
What is contained in the dense fibrillar component of the nucleolus?
 Definition
rRNA molecules actively being synthesized.
Term
What is contained in the granular component of the nucleolus?
 Definition
Maturing ribosomal precursor particles.
Term
What is the primary function of the nucleolus?
 Definition
Ribosome biogenesis.
Term
T or F: The nucleolus is membrane-bound.
 Definition
False.
Term
What do rDNA genes encode?
 Definition
3 of the 4 rRNA species (28S, 18S, and 5.8S) are transcribed as a large 45S precursor. The enzyme that carries out this synthesis is RNA Polymerase I.
Term
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 Definition
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4
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5
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5
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 Definition
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 Definition
15
Term
Chromosome.
 Definition
Extremely long linear polymers of double stranded DNA that carries the genetic information of a eukaryotic organism.
Term
Autosomes.
 Definition
An autosome is a chromosome that is not a sex chromosome, or allosome; that is to say, there is an equal number of copies of the chromosome in males and females. For example, in humans, there are 22 pairs of autosomes.
Term
Sex chromosome (allosome).
 Definition
An allosome is a sex chromosome that differs from an ordinary autosome in form, size, or behavior. The human sex chromosomes are a typical pair of allosomes. The X chromosome is present in the ovum, while X or Y chromosomes can be present in sperm.
Term
How many chromosomes exist in a human diploid nucleus?
 Definition
46 chromosomes: 44 autosomes and 2 sex chromosomes (XX = female, XY = male).
Term
Approximately how many base pairs exist in the haploid genome?
 Definition
~3x10^9 base pairs.
Term
Chromatin.
 Definition
The combination of DNA and structural/regulatory proteins that make up the contents of the nucleus of a cell.
Term
Replication origins.
 Definition
Particular sequence where replication is initiated. Each chromosome has many origins distributed over its entire length.
Term
Centromere.
 Definition
A region of DNA typically found near the middle of a chromosome where two identical sister chromatids come closest in contact. It is involved in cell division as the point of mitotic spindle attachment, thereby allowing for segregation of the duplicated chromosomes at cell division.
Term
Telomeres.
 Definition
A region of repetitive DNA sequences at the end of a chromosome, which protects the end of the chromosome from deterioration or from fusion with neighboring chromosomes. The telomere regions deter the degradation of genes near the ends of chromosomes by allowing for the shortening of chromosome ends, which necessarily occurs during chromosome replication. Telomere sequences contain short tandem repeats, the number of which are maintained by the enzyme telomerase.
Term
Telomerase.
 Definition
An enzyme that adds DNA sequence repeats (GGGGTTA) to the 3' end of DNA strands in the telomere regions, which are found at the ends of eukaryotic chromosomes. This region of repeated nucleotide called telomeres contains non-coding DNA material and prevents constant loss of important DNA from chromosome ends. As a result, every time the chromosome is copied only 100-200 nucleotides are lost, which causes no damage to the organism's DNA. Telomerase is a reverse transcriptase that carries its own RNA molecule, which is used as a template when it elongates telomeres, which are shortened after each replication cycle.
Term
Satellite DNA.
 Definition
Consists of very large arrays of tandemly repeating, non-coding DNA. (Contained in both centromeres and telomeres.)
Term
What portion of the chromosome can't be RNA primed?
 Definition
The 5' ends of the lagging strands.
Term
Junk DNA.
 Definition
The majority of the genome which does not code for anything. Junk DNA can be repetitive (many copies dispersed throughout the genome) or non-repetitive. Some examples of repetitive, junk DNA:
•Alu sequences-old non-functional transposons, highly repetitive and ~5% of the genome.
•Transposons-mobile DNA elements, ~34% of the genome.
•Pseudogenes-non-functional gene replicates.
Term
Gene.
 Definition
A segment of DNA that codes for an RNA species.
Term
What are the major classes of RNA species that are coded by DNA?
 Definition
rRNA, tRNA, and mRNA. (Also Other classes of RNAs include snRNAs and snoRNAs, and more recently micro-RNAs.)
Term
RNA splicing.
 Definition
A modification of an RNA after transcription, in which introns are removed and exons are joined. This is needed for the typical eukaryotic messenger RNA before it can be used to produce a correct protein through translation.
Term
Introns.
 Definition
Any nucleotide sequence within a gene that is removed by RNA splicing to generate the final mature RNA product of a gene.

"Introns are out."
Term
Exons.
 Definition
Nucleotide sequences that are joined together in the final mature RNA after RNA splicing.
Term
What role did the exon/intron system play in evolution.
 Definition
Exons code for functional sub-domains of proteins that can be recombined to create new genes whose products bring together some of the functions of the parent genes.
Term
Chromatin.
 Definition
The sum of chromosomal DNA and its associated proteins (histones and regulatory proteins.
Term
Histones.
 Definition
Abundant, positively charged DNA binding proteins. found in eukaryotic cell nuclei that package and order the DNA into structural units called nucleosomes. They are the chief protein components of chromatin, acting as spools around which DNA winds, and play a role in gene regulation. Without histones, the unwound DNA in chromosomes would be very long (a length to width ratio of more than 10 million to one in human DNA). For example, each human cell has about 1.8 meters of DNA, but wound on the histones it has about 90 micrometers (0.09 mm) of chromatin, which, when duplicated and condensed during mitosis, result in about 120 micrometers of chromosomes.
Term
What are the 5 kinds of major histones involved in elementary chromosome packaging?
 Definition
1) H1
2) H2A
3) H2B
4) H3
5) H4
Term
Euchromatin.
 Definition
Lightly packed form of chromatin (DNA, RNA and protein) that is rich in gene concentration, and is often (but not always) under active transcription.
Term
Heterochromatin.
 Definition
Tightly packed form of chromatin (DNA, RNA and protein) that is not being expressed.
Term
Chromosome condensation.
 Definition
At mitosis, the extremely high level of chromosomal packaging.
Term
When are chromosomes most condensed?
 Definition
At mitosis.
Term
Nucleosome.
 Definition
The basic unit of DNA packaging in eukaryotes, consisting of a segment of DNA wound around a histone protein core. This structure is often compared to thread wrapped around a spool. The nucleosome has a histone core of 2 copies each of histones H2A, H2B, H3, and H4. This histone octomer forms a barrel-like structure around which 146 BPs of DNA are wrapped. Each nucleosome is separated by linker DNA such that ~200 BPs of DNA are packaged per nucleosome resulting in a reduction to about 1/3 of the original length.
Term
What accounts for the interactions between histones and DNA?
 Definition
The positively charged residues on the histones make them well suited for forming tight interactions with negatively charged DNA.
Term
Which histones are involved in the nucleosome? What is this interaction called?
 Definition
Histones H2A, H2B, H3, and H4 are involved in formation of the histone octomer.
Term
How many BPs of DNA are wrapped around each histone octomer?
 Definition
146.
Term
How many BPs of DNA are packaged per nucleosome?
 Definition
Including the linker DNA, ~200 BPs of DNA are packaged per nucleosome.
Term
Nucleosome (image).
 Definition
[image]
Term
What's the width of a nucleosome?
 Definition
11 nm.
Term
Histone H1.
 Definition
One histone H1 is associated with each nucleosome. Histone H1 coils the nucleosome into a 30 nm fiber.
Term
The 30 nm chromatin fiber.
 Definition
Comprised of nucleosomes wrapped by one copy of histone H1. Sequence specific DNA-binding proteins can disrupt chromatin structure to allow for access and expression of genes within packaged chromatin.
Term
N-terminus.
 Definition
The N-terminus refers to the start of a protein or polypeptide terminated by an amino acid with a free amine group (-NH2). The convention for writing peptide sequences is to put the N-terminus on the left and write the sequence from N- to C-terminus. When the protein is translated from messenger RNA, it is created from N-terminus to C-terminus.
Term
The histone tails.
 Definition
The histone N-terminal tails protrude from the nucleosome. Lysine residues in the tails can modified by methylation and acetylation. Patterns of acetylation are regulated and are metastable in that they can persist through many cell divisions. Acetylation locally alters chromatin structure and protein composition affecting accessibility to, or the recruiting of, regulatory proteins.
Term
Which residues on the histone tails can be modified by methylation?
 Definition
Lysine residues.
Term
Methylation.
 Definition
The addition of a methyl group (-CH3) to a substrate.
Term
Acetylation.
 Definition
The addition of an acetyl group (-COCH3) to a substrate. Patterns of acetylation are regulated and are metastable in that they can persist through many cell divisions. Acetylation locally alters chromatin structure and protein composition affecting accessibility to, or the recruiting of, regulatory proteins. This process is regulated by a diverse set of histone acetylases and de-acetylases.
Term
What is the practical significance that mitotic chromosomes, when stained with certain dyes, will adopt characteristic banding patterns?
 Definition
The banding patterns allow for the identification of the chromosomes and a determination of their normality. Cytogeneticists use this procedure to analyze chromosomes to determine any gross defects in chromosome structure and/or non-disjunction events.
Term
Which residues on the histone tails can be modified by phosphorylation?
 Definition
Serines.
Term
Nuclear matrix.
 Definition
An underlying fibrous network (made largely of proteins) that facilitates further organization of the nucleus. (Analogous to the cell cytoskeleton.) This organization leads to chromosomes occupying distinct territories within the nucleus; chromosomes are not tangled like a bowl of spaghetti.
Term
Matrix-Associated Regions (MARs).
 Definition
Sequences in the DNA of eukaryotic chromosomes where the nuclear matrix attaches. Regions of chromosomes that are being actively transcribed (euchromatin) are brought together in a relatively small number of foci that serve as transcription/splicing factories. There are open channels to the nuclear pores so that newly synthesized RNAs can be moved to the periphery and transported (when appropriate) to the cytoplasm.
Term
Nuclear breakdown at mitosis.
 Definition
All transcriptional activity ceases at mitosis, leading to dissolution of the nucleolus followed by chromosome condensation. Phosphorylation of the lamin proteins induces disassembly of the nuclear lamina that in turn causes the nuclear envelope to break down into vesicles.
Term
Nuclear reformation following mitosis.
 Definition
The lamins are de-phosphorylated and the nuclear matrix and nuclear envelope reassembles around each de-condensing chromosome. The chromosomes then fuse to recreate a complete nucleus. Transcription of rDNA resumes which creates 10 pre-nucleolar foci that subsequently fuse to reform the nucleolus.
Term
Systemic lupus erythematousus.
(Lupus)
 Definition
An autoimmune disease of mysterious genesis that leads to inflammation and tissue damage most frequently to the joints and skin. SLE is caused by the production of antibodies to self-antigens in the nucleus. Individual SLE patients have been observed to have antibodies to splicing factors, nuclear pore proteins, or even DNA itself.
Term
Acute promyelocytic leukemia.
 Definition
Initially manifests itself as a severe bleeding disorder due to a reciprocal translocation that fuses the retinoic acid receptor to the nuclear protein PML creating altered activities. The mutation in the nuclear protein PML disallows the protein to form sub-compartments in the nucleus.
Term
Spinal muscular atrophy.
 Definition
Frequently inherited, caused by mutations in the protein SMN (survival of motor neurons) that is part of a protein complex believed to be involved in RNA splicing. This is the 2nd most common neuromuscular disease of childhood to Duchenne muscular distrophy.
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