Transcript Tumor-Suppressor Genes

Overview: How Eukaryotic Genomes Work and
Evolve
• Two features of eukaryotic genomes are a major
information-processing challenge:
– First, the typical eukaryotic genome is much
larger than that of a prokaryotic cell
– Second, cell specialization limits the
expression of many genes to specific cells
• The DNA-protein complex, called chromatin, is
ordered into higher structural levels than the DNAprotein complex in prokaryotes
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Concept 19.1: Chromatin structure is based on
successive levels of DNA packing
• Eukaryotic DNA is precisely combined with a large
amount of protein
• Eukaryotic chromosomes contain an enormous
amount of DNA relative to their condensed length
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Nucleosomes, or “Beads on a String”
• Proteins called histones are responsible for the
first level of DNA packing in chromatin
• The association of DNA and histones seems to
remain intact throughout the cell cycle
• In electron micrographs, unfolded chromatin has
the appearance of beads on a string
• Each “bead” is a nucleosome, the basic unit of
DNA packing
Animation: DNA Packing
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LE 19-2a
2 nm
DNA double helix
Histones
Histone
tails
Histone H1
Linker DNA
(“string”)
Nucleosome
(“bead”)
Nucleosomes (10-nm fiber)
10 nm
Higher Levels of DNA Packing
• The next level of packing forms the 30-nm
chromatin fiber
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LE 19-2b
30 nm
Nucleosome
30-nm fiber
• In turn, the 30-nm fiber forms looped domains,
making up a 300-nm fiber
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LE 19-2c
Protein scaffold
Loops
300 nm
Looped domains (300-nm fiber)
Scaffold
• In a mitotic chromosome, the looped domains coil
and fold, forming the metaphase chromosome
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LE 19-2d
700 nm
1,400 nm
Metaphase chromosome
• Interphase chromatin is usually much less
condensed than that of mitotic chromosomes
• Much of the interphase chromatin is present as a
10-nm fiber, and some is 30-nm fiber, which in
some regions is folded into looped domains
• Interphase chromosomes have highly condensed
areas, called heterochromatin, and less
compacted areas, called euchromatin
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Concept 19.2: Gene expression can be regulated at
any stage, but the key step is transcription
• All organisms must regulate which genes are
expressed at any given time
• A multicellular organism’s cells undergo cell
differentiation, specialization in form and function
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Differential Gene Expression
• Differences between cell types result from
differential gene expression, the expression of
different genes by cells within the same genome
• In each type of differentiated cell, a unique subset
of genes is expressed
• Many key stages of gene expression can be
regulated in eukaryotic cells
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LE 19-3
Signal
NUCLEUS
Chromatin
DNA
Gene available
for transcription
Gene
Transcription
RNA
Exon
Primary transcript
Intro
RNA processing
Tail
Cap
mRNA in nucleus
Transport to cytoplasm
CYTOPLASM
mRNA in cytoplasm
Degradation
of mRNA
Translation
Polypeptide
Cleavage
Chemical modification
Transport to cellular
destination
Active protein
Degradation of protein
Degraded protein
DNA Methylation
• DNA methylation, the addition of methyl groups to
certain bases in DNA, is associated with reduced
transcription in some species
• In some species, DNA methylation causes longterm inactivation of genes in cellular differentiation
• In genomic imprinting, methylation turns off either
the maternal or paternal alleles of certain genes at
the start of development
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Epigenetic Inheritance
• Although the chromatin modifications just
discussed do not alter DNA sequence, they may
be passed to future generations of cells
• The inheritance of traits transmitted by
mechanisms not directly involving the nucleotide
sequence is called epigenetic inheritance
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Regulation of Transcription Initiation
• Chromatin-modifying enzymes provide initial
control of gene expression by making a region of
DNA either more or less able to bind the
transcription machinery
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The Roles of Transcription Factors
• To initiate transcription, eukaryotic RNA
polymerase requires the assistance of proteins
called transcription factors
• General transcription factors are essential for the
transcription of all protein-coding genes
• In eukaryotes, high levels of transcription of
particular genes depend on control elements
interacting with specific transcription factors
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Enhancers and Specific Transcription Factors
• Proximal control elements are located close to the
promoter
• Distal control elements, groups of which are called
enhancers, may be far away from a gene or even
in an intron
• An activator is a protein that binds to an enhancer
and stimulates transcription of a gene
Animation: Initiation of Transcription
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LE 19-6
Distal control
element
Activators
Promoter
Gene
DNA
TATA
box
Enhancer
General
transcription
factors
DNA-bending
protein
Group of
mediator proteins
RNA
polymerase II
RNA
polymerase II
Transcription
Initiation complex
RNA synthesis
• Some transcription factors function as repressors,
inhibiting expression of a particular gene
• Some activators and repressors act indirectly by
influencing chromatin structure
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Coordinately Controlled Genes
• Unlike the genes of a prokaryotic operon,
coordinately controlled eukaryotic genes each
have a promoter and control elements
• The same regulatory sequences are common to
all the genes of a group, enabling recognition by
the same specific transcription factors
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Mechanisms of Post-Transcriptional Regulation
• Transcription alone does not account for gene
expression
• More and more examples are being found of
regulatory mechanisms that operate at various
stages after transcription
• Such mechanisms allow a cell to fine-tune gene
expression rapidly in response to environmental
changes
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RNA Processing
• In alternative RNA splicing, different mRNA
molecules are produced from the same primary
transcript, depending on which RNA segments are
treated as exons and which as introns
Animation: RNA Processing
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LE 19-8
Exons
DNA
Primary
RNA
transcript
RNA splicing
mRNA
or
mRNA Degradation
• The life span of mRNA molecules in the cytoplasm
is a key to determining the protein synthesis
• The mRNA life span is determined in part by
sequences in the leader and trailer regions
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Initiation of Translation
• The initiation of translation of selected
mRNAs can be blocked by regulatory proteins that
bind to sequences or structures of the mRNA
• Alternatively, translation of all mRNAs
in a cell may be regulated simultaneously
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Protein Processing and Degradation
• After translation, various types of protein
processing, including cleavage and the addition of
chemical groups, are subject to control
• Proteasomes are giant protein complexes that
bind protein molecules and degrade them
Animation: Protein Processing
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Animation: Protein Degradation
LE 19-10
Proteasome
and ubiquitin
to be recycled
Ubiquitin
Proteasome
Protein to
be degraded
Ubiquitinated
protein
Protein entering a
proteasome
Protein
fragments
(peptides)
Concept 19.3: Cancer results from genetic changes
that affect cell cycle control
• The gene regulation systems that go wrong during
cancer are very same systems that play important
roles in embryonic development
• Thus, research into the molecular basis of cancer
has benefited from and informed many other fields
of biology
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Types of Genes Associated with Cancer
• Genes that normally regulate cell growth and
division during the cell cycle include:
– Genes for growth factors
– Their receptors
– Intracellular molecules of signaling pathways
• Mutations altering any of these genes in somatic
cells can lead to cancer
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Oncogenes and Proto-Oncogenes
• Oncogenes are cancer-causing genes
• Proto-oncogenes are normal cellular genes that
code for proteins that stimulate normal cell growth
and division
• A DNA change that makes a proto-oncogene
excessively active converts it to an oncogene,
which may promote excessive cell division and
cancer
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LE 19-11
Proto-oncogene
DNA
Translocation or transposition:
gene moved to new locus,
under new controls
Gene amplification:
multiple copies of the gene
New
promoter
Normal growth-stimulating
protein in excess
Point mutation
within a control
element
Oncogene
Normal growth-stimulating
protein in excess
Normal growth-stimulating
protein in excess
Point mutation
within the gene
Oncogene
Hyperactive or
degradationresistant protein
Tumor-Suppressor Genes
• Tumor-suppressor genes encode proteins that
inhibit abnormal cell division
• Any decrease in the normal activity of a tumorsuppressor protein may contribute to cancer
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The Multistep Model of Cancer Development
• More than one somatic mutation is generally
needed to produce a full-fledged cancer cell
• About a half dozen DNA changes must occur for a
cell to become fully cancerous
• These changes usually include at least one active
oncogene and mutation or loss of several tumorsuppressor genes
• Colorectal cancer, with 135,000 new cases and
60,000 deaths in the United States each year,
illustrates a multistep cancer path
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LE 19-13
Colon
Normal colon
epithelial cells
Loss of
tumorsuppressor
gene p53
Activation of
ras oncogene
Loss of
tumorsuppressor
Colon wall gene APC (or
other)
Small benign
growth (polyp)
Loss of
tumorsuppressor
gene DCC
Additional
mutations
Larger benign
growth (adenoma)
Malignant tumor
(carcinoma)
• Certain viruses promote cancer by integration of
viral DNA into a cell’s genome
• By this process, a retrovirus may donate an
oncogene to the cell
• Viruses seem to play a role in about 15% of
human cancer cases worldwide
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Inherited Predisposition to Cancer
• The fact that multiple genetic changes are
required to produce a cancer cell helps explain the
predispositions to cancer that run in some families
• Individuals who inherit a mutant oncogene or
tumor-suppressor allele have an increased risk of
developing certain types of cancer
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Concept 19.4: Eukaryotic genomes can have many
noncoding DNA sequences in addition to genes
• The bulk of most eukaryotic genomes consists of
noncoding DNA sequences, often described in the
past as “junk DNA”
• However, much evidence is accumulating that
noncoding DNA plays important roles in the cell
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The Relationship Between Genomic Composition
and Organismal Complexity
• Compared with prokaryotic genomes, the
genomes of eukaryotes:
– Generally are larger
– Have longer genes
– Contain much more noncoding DNA
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• The sequencing of the human genome reveals
what makes up most of the 98.5% of the genome
that does not code for proteins, rRNAs, or tRNAs
• Most intergenic DNA is repetitive DNA, present in
multiple copies in the genome
• About three-fourths of repetitive DNA is made up
of transposable elements and sequences related
to them
Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings
LE 19-14
Exons (regions of genes coding
for protein, rRNA, or tRNA) (1.5%)
Repetitive
DNA that
includes
transposable
elements
and related
sequences
(44%)
Introns and
regulatory
sequences
(24%)
Repetitive
DNA
unrelated to
transposable
elements
(about 15%)
Unique
noncoding
DNA (15%)
Alu elements
(10%)
Simple sequence
DNA (3%)
Large-segment
duplications (5–6%)
Transposable Elements and Related Sequences
• The first evidence for wandering DNA segments
came from geneticist Barbara McClintock’s
breeding experiments with Indian corn
• McClintock identified changes in the color of corn
kernels that made sense only by postulating that
some genetic elements move from other genome
locations into the genes for kernel color
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Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings
Movement of Transposons and Retrotransposons
• Eukaryotic transposable elements are of two
types:
– Transposons, which move within a genome by
means of a DNA intermediate
– Retrotransposons, which move by means of an
RNA intermediate
Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings
Genes and Multigene Families
• Most eukaryotic genes are present in one copy
per haploid set of chromosomes
• The rest of the genome occurs in multigene
families, collections of identical or very similar
genes
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• The classic examples of multigene families of
nonidentical genes are two related families of
genes that encode globins
• Globin gene family clusters also include
pseudogenes, nonfunctional nucleotide
sequences that are similar to the functional genes
Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings
Concept 19.5: Duplications, rearrangements, and
mutations of DNA contribute to genome evolution
• The basis of change at the genomic level is
mutation, underlying much of genome evolution
• The earliest forms of life likely had a minimal
number of genes, including only those necessary
for survival and reproduction
• The size of genomes has increased over
evolutionary time, with the extra genetic material
providing raw material for gene diversification
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Duplication of Chromosome Sets
• Accidents in meiosis can lead to one or more extra
sets of chromosomes, a condition known as
polyploidy
• The genes in one or more of the extra sets can
diverge by accumulating mutations; these
variations may persist if the organism carrying
them survives and reproduces
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Duplication and Divergence of DNA Segments
• Unequal crossing over during prophase I of
meiosis can result in one chromosome with a
deletion and another with a duplication of a
particular region
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LE 19-18
Transposable
element
Gene
Nonsister
chromatids
Crossover
Incorrect pairing
of two homologues
during meiosis
and
Evolution of Genes with Related Functions: The
Human Globin Genes
• The genes encoding the various globin proteins
evolved from one common ancestral globin gene,
which duplicated and diverged
• After the duplication events, differences between
the genes in the globin family arose from
mutations that accumulated in the gene copies
over many generations
Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings
LE 19-19
Ancestral globin gene
Duplication of
ancestral gene
Mutation in
both copies

Transposition
to different
chromosomes


Further
duplications
and mutations





  1 2
1 
-Globin gene family
on chromosome 16


A


-Globin gene family
on chromosome 11

• Subsequent duplications of these genes and
random mutations gave rise to the present globin
genes, which code for oxygen-binding proteins
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• The similarity in the amino acid sequences of the
various globin proteins supports this model of
gene duplication and mutation
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Evolution of Genes with Novel Functions
• The copies of some duplicated genes have
diverged so much in evolution that the functions of
their encoded proteins are now very different
Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings