Chromosome Parts

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Chromosome Parts - Origins, Centromeres,
Telomeres
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Every chromosome has to contains one centromere,
two telomeres, and multiple origins of
replication
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Every chromosome has multiple origins of
replication. These origins fire only once per
cell cycle
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Euchromatic and Heterochromatic
regions replicate at different times during S
phase. Euchromatin - early Heterochromatin - late
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Every chromosome has to contains one centromere,
two telomeres, and multiple origins of
replication
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Centromeres are required for the segregation of
chromosomes during mitosis
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Mitotic chromosome condensation is driven by
ATPases called Condensins
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Organization of a Centromere
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Centromeric Heterochromatin contains special
nucleosomes
CENP-A
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Every chromosome has to contains one centromere,
two telomeres, and multiple origins of
replication
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Chromosome Ends are specialized structures called
Telomeres
Blue chromosomes White Telomere protein
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Telomeres
Repeated G rich sequence on one strand in
humans (TTAGGG)n Repeats can be several
thousand basepairs long. In humans, telomeric
repeats average 5-15 kilobases Telomere specific
proteins, eg. TRF1 TRF2 bind to the repeat
sequence and protect the ends Without these
proteins, telomeres are acted upon by DNA repair
pathways leading to chromosomal fusions
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The End Replication Problem
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The end replication problem leads to loss of
information from opposite strands at both ends
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Without some form of correction the end
replication problem leads to the loss of 50-100
nucleotides from the newly synthesized lagging
strand at each chromosome end in each round of
duplication
In mammalian (and many other) cells, the solution
to this problem is that chromosome ends have a
special duplication machinery Telomerase
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• Different types of Nucleotide Polymerases
• DNA polymerase
• Uses a DNA template to synthesize a DNA
  strand

2) RNA polymerase Uses a DNA template to
synthesize an RNA strand ( transcription) 3)
Reverse transcriptase Uses an RNA template to
synthesize a DNA strand Found in many
viruses Telomerase is a specialized reverse
transcriptase
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Telomerase is composed of both RNA and protein
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? and Primase
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Telomeres are packaged into a unique structure
-- a T-loop
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T-loop seen in the electron microscope
Green Telomere-specific proteins
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Telomerase and Senescence
In most somatic tissues, telomerase is expressed
at very low levels or not at all -- as cells
divide, telomeres shorten
Short telomeres may be a signal for cells to
senesce (stop dividing)
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Evidence that shortening of telomeres may be a
signal to stop cellular division -Primary cells
taken from the body and grown in vitro will
divide a few times and then stop. If the gene
encoding the catalytic subunit of Telomerase is
expressed in these primary cells, they grow for
many more divisions. -Proliferating cells in
the body (stem cells / germ cells) express
telomerase -Cancer cells express telomerase
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Telomerase and Cancer
The presence of telomerase in cancer cells allows
them to maintain telomere length while they
proliferate
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Telomerase and Cancer
Could turning off telomerase in cancer cells
cause them to senesce and thereby stop
progression of the disease? Maybe Studies in an
important model system, Telomerase deficient
mice indicate that it will probably depend on the
type of tumor.
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Short telomeres cause growth arrest via a
checkpoint
Sensed as DNA damage by the p53 checkpoint
Stops Cell Division
If the cells of a particular tumor still have
p53, this works
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Buttumor cells often lack p53
Sensed as DNA damage by the p53 checkpoint
Cell division continues without telomeres leading
to chromosomal rearrangements
This genomic instability can promote
tumorigenesis
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Telomerase and Aging
Because there is very little telomerase in
somatic tissues, older people have shorter
telomeres -particularly in actively regenerating
tissues such as skin or intestinal
ephithelia This has generated a lot of interest
in the possibility that telomere length could be
tied to aging
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Aging (mean life span) is influenced by
environmental factors
E.g. Caloric Restriction Rodents kept on a very
restricted calorie diet live, on average about
35 longer than control animals maintained on
full diet. Restricted diet is roughly the
equivalent of a human living on 600
calories/day In lower organisms such as
roundworms or yeast, caloric restriction also
increases lifespan
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Aging (mean life span) is also influenced by
genetic traits
Specific mutations have been identified in model
organisms such as worms, flies, and yeast that
lead to extension of lifespan
Analysis of such mutants holds out the
possibility of understanding the molecular
mechanisms of aging
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One such mutant that affects lifespan has been
proposed as a possible connection between
telomeres, metabolism and aging -- Sir2
Sir2 was originally identified in yeast. It
encodes a component of heterochromatin and
localizes to telomeres It is an enzyme required
for the formation of heterochromatin in yeast
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Sir2 is part of this complex that binds to
deacetylated histone tails
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Sir2 is an NAD-dependent histone deacetylase

SIR2
Nicotinamide ADP-Ribose
NAD
NAD is not used as an electron acceptor, it is
consumed in the reaction
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Sir2 related proteins are found in all
eukaryotes, including man The family of proteins
are referred to as Sirtuins
-Yeast mutants lacking SIR2 have a shorter
lifespan -The same is true for C. elegans (worms)
lacking the SIR2 homolog -The human homolog
enhances survival of cells in culture
The mechanism by which Sir2 promotes longevity
is unknown but general idea is this
Aging
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Because it consumes NAD, SIR2 has been proposed
to be the monitor that connects metabolism to
aging
High Calorie Diet NAD is converted to NADH
unavailable for SIR2
Caloric Restriction Less NAD used in
catabolism More available for SIR2 action
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Science-wise this should all be taken with a
grain of salt at this point. So why should you
care?
Resveratrol, a polyphenolic compound found in red
wines acts as an allosteric activator of
Sirtuins. Coming soon to an unregulated
nutritional supplement near you