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Transcript
• DNA and
Chromosomes
Genes are carried by
Chromosomes
Two plant cells visualized by
light microscope, DNA stained
with DAPI
Chromosome in Cells
DNA (deoxyribonucleic acid)
AGTC
Human 46 chromosomes
22 homologs, x, or x/y
Experimental procedures demonstrating that DNA is the genetic material
1940s
The Structure and Function of DNA
• Genetic information is carried in the linear sequence of
nucleotides in DNA
• Genetic information contains instructions to synthesize
proteins
• DNA forms double helix with two complimentary strands
holding together by hydrogen bonds between A-T (2
bonds) and G-C (3 bonds)
• DNA duplication occurs using one strand of parental DNA
as template to form complimentary pairs with a new DNA
strand.
• DNA is in nucleus in eucaryotes
1953 Watson and Crick
determined the structure of DNA
DNA and its Building
Nucleotides: Guanine (G),
Adenine (A), Cytosine (C),
Thymine (T).
Polarized strand, 5’->3’
Base inside, sugar outside
DNA and its Building
Antiparallel strands
DNA Pairs
A always pairs with T,
and G with C,
A-T two hydrogen
bonds, G-C three
hydrogen bonds
DNA Double Helix
10.4 nucleutides/turn; 3.4 nm between nucleutides
DNA to Protein
Genome: the complete set of information in an organism’s DNA
Total length of DNA about 2 meters long in a human cell, encoding
about 30000 proteins
To carry the genomic information to daughter cells
DNA Duplication
Using itself as template
Cell Nucleus, compartmentalized
DNA activity
Nuclear pores allow communication
Nuclear lamina and cytoskeleton
mechanically support the nucleus
Chromosomal DNA and its Packaging
• A gene is a nucleotide sequene in a DNA molecule that act as a
functional unit for protein production, RNA synthesis.
• Introns and Exons
• Chromosome: single long DNA contains a linear array of
many genes.
• Human genome contains 2.3x109 DNA nucleotide pairs, with
22 different autosomes and 2 sex chromosomes.
• Chromosomal DNA: replication origins, telomeres,
centromeres
• Histones form the protein core for DNA wrapping
• Nucleosome: repeating array of DNA-protein particles
• Modification of Chromatin and nucleosomes: histone H1,
ATP-driven chromatin remodeling complexes, and
enzymatically catalyzed covalent modification of the Nterminal tails of Histones
Human Chromosome
Complex of DNA and protein is called chromatin
44 homologous chromosomes and 2 sex chromosomes
Complementary DNA with different Dyes
The arrangement of the full chromosome set is called karyotype
Banding Pattern of
human chromosomes
Giemsa Staining
Green line regions:
centromeres
Encoding ribosome
The organization of genes of a human chromosome
Conservation between human and mouse genomes
Usually important genes are encoded by conserved regions
Note: Human chromosome 1 and mouse chromosome 4
mouse
human
centromere
Cell Cycle
DNA molecule not only carries genetic information, but also undergoes
conformational change
Chromosomes exist through the cycle
Mitotic and interphase chromosome
Single chromosome can only be visible during mitosis
Chromosomes at
interphase and M
phase
Three important DNA sequences
Telomere, replication origin, centromere
DNA Molecules are highly condensed in chromosomes
Nucleosomes of interphase under electron microscope
Nucleosome: basic level of chromosome/chromatin organization
Chromatin: protein-DNA complex
Histone: DNA binding protein
A: diameter 30 nm; B: further unfolding, beads on a string conformation
Nucleosome Structures
Histone octamer
2 H2A
2 H2B
2 H3
2 H4
X-ray diffraction analyses of crystals
Structure of a nucleosome core particle
Structural Organization of the Core Histones
The Assembly of the Core Histones
Notice the long tails of the octamer
The bending of DNA in a nucleosome
1. Flexibility of DNAs: A-T riched minor groove inside and G-C
riched groove outside
2. DNA bound protein can also help
Zigzag model of the 30-nm chromatin fiber
Irregularities in the 30-nm fiber
Flexible linker, DNA binding proteins
Structural modulators: H1 histone, ATP-driven Chromatin remodeling
machine, covalent modification of histone tails
The function of Histone H1
The function of
Histone tails
Chromatin Remodeling
Cyclic Diagram for
nucleosome formation and
disruption
Covalent Modification
of core histone tails
Acetylation of lysines
Mythylation of lysines
Phosphorylation of
serines
Histone acetyl
transferase (HAT)
Histone deacetylase
(HDAC)
Summary
•
•
•
•
•
•
DNA, Chromosome
Centromere, telomere, replication origin
Nucleosome, Chromatin,
Histone: H1, H2A, H2B, H3, H4
Histone octamer, DNA packaging
DNA binding proteins, Histone
modifications
The Global Structure of Chromosomes
• Some rare cases of interphase
chromosomes, certain features maybe
universal
• Representative forms forming typical
interphase chromosome
• Chromosome at mitosis
Lampbrush chromosomes (amphibian oocyte, immature eggs)
A model for the structure of a
lampbrush chromosome
Chromomeres: highly condensed
and in general not expressed until
unfolding
A polytene chromosome from
Drosophila salivary gland
Dark bands and interbands
Electron Microscope image of Drosophila polytene chromosome
Chromosome puffs
Folding and refolding at a time
course of 22 hours
RNA synthesis in Chromosome puffs
Red: newly synthesized BrUTP; Blue: old ones diffused
RNA synthesis in Chromosome puffs
RNA synthesis in Chromosome puffs
Model of RNA synthesis in Chromosome puffs
A model for the structure of an
interphase chromosome
Position Effects on Gene
Expression
Heterochromatin: condensed
Euchromatin: loose
Speculative Model for the heterochromatin at the ends of yeast
chromosomes
Sir: Silent information regulator binding to unacetylated histone tails
Speculative Model for the heterochromatin at the ends of yeast
chromosomes
DNA-binding proteins recognize DNA sequence close to telomere, recruit
Sir proteins and cause histone tail modification, forming heterochromatin
Two speculative models for how the tight packaging of DNA in
heterochromatin can be inherited during chromosome replication
The specialized nucleosome formed on centromeres
Also belongs to heterochromatin
The structure of a human
centromere
1. Alpha satellite DNA
sequence
2. Kinetochore inner plate
3. Kinetochore outer plate
4. Spindle microtubules
The plasticity of human centromere formation
A typical mitotic chromosome at
metaphase
SEM of a region near one
end of a typical mitotic
chromosome
EM of a mitotic
chromosome
Chromatin Packing
Condensin plays important roles
The SMC (Structural Maintenance
of Chromosomes) proteins in
condensins
Selective localization of two interphase chromosomes
Chromosome 18 (red) and 19 (turquoise)
Specific regions of interphase chromosomes in close proximity to the
nuclear envelope
Two different regions of chromosome 2 (yellow and magenta) close to
the nuclear envelop (green)
Summary
• Chromosomes are decondensed during interphase and
hard to visualize
• Lampbrush chromosomes of vertebrate oocytes and
polytene chromosomes in the giant secretory cells of
insects are exceptions, revealing the global
organization of chromosome
• Gene expression needs the decondensation of
chromosome loops
• Euchromatin and heterochromatin
• Telomere and centromere are general heterochromatin
• Chromosomes are spatially organized and deposited in
nucleus
• Mitotic chromosomes are condensed and organized.