telomeres what are they? why are they important?
DESCRIPTION
TELOMERES What are they? Why are they important? Telomere shortening and the end-replication problem Telomerase Telomere hypothesis of aging. Telomeres Ends of linear chromosomes. Centromere. Telomere. Telomere. Repetitive DNA sequence (TTAGGG in vertebrates) Specialized proteins - PowerPoint PPT PresentationTRANSCRIPT
TELOMERES
What are they?
Why are they important?
Telomere shortening and the end-replication problem
Telomerase
Telomere hypothesis of aging
Telomeres
Ends of linear chromosomes
Centromere
TelomereTelomere
Repetitive DNA sequence(TTAGGG in vertebrates)
Specialized proteins
Form a 'capped' end structure
Telomeres 'cap' chromosome ends
TELOMERE STRUCTURE
5’ 3’
5'
3'
Telomerict loop
Telomericproteins:
TRF1TRF2TIN2RAP1
TANKS 1,2POT1
etc
NUCLEARMATRIX
Why are telomeres important?
Telomeres allow cells to distinguish chromosomesends 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)
Why are telomeres important?Prevent chromosome fusions by NHEJ (non-homologous end joining)
NHEJ
Mitosis
FUSIONBRIDGE
BREAKAGE
Fusion-bridge-breakage cycles
Genomic instability
Cell death OR neoplastic transformation
Telomere also provide a means for "counting" cell division
Pro
lifer
ativ
e ca
paci
ty
Number of cell divisions
FiniteReplicativeLife Span"Mortal"
InfiniteReplicativeLife Span"Immortal"
How do cells "know" how many divisions they have completed??
The End Replication Problem:Telomeres shorten with each S phase
OriDNA replication is bidirectional
Polymerases move 5' to 3'
Requires a labile primer
3'5'
3'5'
5'
5' 3'3' 5'
Each round of DNAreplication leaves
50-200 bp DNA unreplicatedat the 3' end
Telomere Length (humans)
Number of Doublings
20
10
Cellular (Replicative) Senescence
Normal Somatic Cells
(Telomerase Negative)
Telomere also provide a means for "counting" cell division: telomeres shorten with each cycle
Telomeres shorten from 10-15 kb(germ line) to 3-5 kb after 50-60 doublings
(average lengths of TRFs)
Cellular senescence is triggered whencells acquire one or a few critically short telomeres.
How do replicatively immortal cells
avoid complete loss of telomeres
(how do they solve the end-replication problem)?
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 end-replication 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 cellsRemaining still need to overcome the end replication problem;
do so by recombinational mechanisms -- ALT (alternative lengthening of telomeres) mechanisms
Telomere Length (humans)
Number of Doublings
20
10
Cellular (Replicative) Senescence
Normal Somatic Cells
(Telomerase Negative)
Germ Cells (Telomerase Positive)
+ Telomerase
Telomere Length and Cell Division Potential
HOWEVER,
CELLS THAT EXPRESS TELOMERASE
STILL UNDERGO SENESCENCE
(E.G., IN RESPONSE TO DNA DAMAGE, ONCOGENES, ETC.)
Inducers of cellular senescenceCell proliferation(short telomeres)
DNA damage OncogenesStrong 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
TRUE
Short telomeres cause cell senescence andsenescent cells may contribute to aging
TRUE
HYPOTHESIS:Telomere shortening causes aging and
telomerase will prevent agingTRUE 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 replicativesenescence but not senescence induce by
other causes
SUMMARY
Telomeres are essential for chromosome stability
Telomere shortening occurs owing to the biochemistry ofDNA replication
Short telomeres cause replicative senescence (other senescence causes are telomere-independent)
Telomerase prevents telomere shortening andreplicative senescence
The telomere hypothesis of aging depends on the cellular senescence hypothesis of aging