Download 9- Telomeres and Telomerase

18th Lecture
TELOMERES &TELOMERASE
Gihan E-H Gawish, MSc, PhD
Ass. Professor
Molecular Genetics and
Clinical Biochemistry
KSU
TELOMERES
What are they?
Why are they important?
Telomere shortening and the
end-replication problem
Telomerase
Telomere hypothesis of aging
Telomeres
Animation
Ends of linear chromosomes
Centromere
Telomere
Telomere
Repetitive DNA sequence
(TTAGGG in vertebrates)
Specialized proteins
Form a 'capped' end structure
Telomeres 'cap' chromosome ends
TELOMERE STRUCTURE
5’
3’
Telomeric
t loop
5'
3'
NUCLEAR
MATRIX
Telomeric
proteins:
TRF1
TRF2
TIN2
RAP1
TANKS 1,2
POT1
etc
Why are telomeres important?
Telomeres allow cells to distinguish chromosomes
ends from broken DNA
Stop cell cycle!
Repair or die!!
Homologous recombination
(error free, but need nearby homologue)
Non-homologous end joining
(any time, but error-prone)
TELOMERASE:
Key to replicative immortality
Enzyme (reverse transcriptase) with
RNA and protein components
Adds telomeric repeat DNA directly to
3' overhang (uses its own RNA as a template)
Vertebrate repeat DNA on 3' end:
TTAGGG
Telomerase RNA template:
AAUCCC
TELOMERASE:
Key to replicative immortality
+ TELOMERASE
Overcomes telomere shortening and the endreplication problem
Expressed by germ cells, early embryonic cells
Not expressed by most somatic cells (human)
May be expressed by some stem cells, but highly controlled
Expressed by 80-90% of cancer cells
Remaining still need to overcome the end replication problem;
do so by recombinational mechanisms -ALT (alternative lengthening of telomeres) mechanisms
Telomere Length and Cell Division Potential
Telomere Length (humans)
20
10
Germ Cells (Telomerase Positive)
Normal
Somatic
Cells
+ Telomerase
(Telomerase
Negative)
Cellular (Replicative) Senescence
Number of Doublings
HOWEVER,
CELLS THAT EXPRESS TELOMERASE
STILL UNDERGO SENESCENCE
(E.G., IN RESPONSE TO DNA
DAMAGE, ONCOGENES, ETC.)
Animation
Inducers of cellular senescence
Cell proliferation
(short telomeres)
DNA damage
Oncogenes
Strong mitogens/
stress
Potential Cancer Causing Events
Telomerase:
Biomedical uses
Expand cells for replacement therapies
(burns, joint replacements, etc)
Telomerase inhibitors to selectively kill cancer cells
The telomere hypothesis of aging
Telomeres shorten with each cell division
and therefore with age
Short telomeres cause cell senescence and
senescent cells may contribute to aging
HYPOTHESIS:
Telomere shortening causes aging and
telomerase will prevent aging
TRUE OR FALSE?
The telomere hypothesis of aging
Telomere length is not related to life span
(mice vs human; M musculus vs M spretus)
Telomeres contribute to aging ONLY if
senescent cells contribute to aging
Telomerase protects against replicative
senescence but not senescence induce by
other causes
SUMMARY -click to find the attached fileTelomeres are essential for chromosome stability
Telomere shortening occurs owing to the biochemistry of
DNA replication
Short telomeres cause replicative senescence
(other senescence causes are telomere-independent)
Telomerase prevents telomere shortening and
replicative senescence
The telomere hypothesis of aging depends on the
cellular senescence hypothesis of aging