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Polymerases at the
replication fork
• semiconservative
• discontinuous
• replication fork geometry
• newly synthesized leading &
lagging strands
• all enzymes
• nucleic acid polarity
1
• all nucleic acids are synthesized in the 5’->3’ direction
221 S16
Prokaryotic and eukaryotic DNA replication forks
have similar replication machines
telomeres
……TTAGGG - 3’
……AATCCC - 5’
3
221 S16
Linear chromosomes: end replication problem at the telomere
4
221 S16
The telomere length declines with age.
……TTAGGG - 3’
……AATCCC - 5’
6
221 S16
<- cell doublings
7
221 S16
8
221 S16
9
221 S16
Tetrahymena thermophila (ciliate)
11
221 S16
Telomerase - reverse transcriptase [1]
12
221 S16
Tetrahymena telomeres
5’ – TTGGGG – 3’
3’ – AACCCC – 5’
3’ AACCC 5’
5’ TTGGGGTTGGGGTTGGGGTTGGGG 3’
13
221 S16
Telomere lengthening: step 1
Tetrahymena sequence
……TTGGGG - 3’
……AACCCC - 5’
Human sequence
……TTAGGG - 3’
……AATCCC - 5’
14
221 S16
Telomere lengthening: step 2 FILL IN THE GAP
15
221 S16
Shelterin shapes & protects telomeres
Shelterin: heterohexamer of
6 different proteins
t-loop shelterin
100-200 nucleotides
16
Genes Dev.19: 2100-2110 (2005) Nature Reviews Cancer 8: 450-458 (2008)
221 S16
Telomere loops: 3’-overhang strand invasion to form D-loop
Post class addition
5’
AGGGTTAGGGT
T T
T A
5’---TTAGGG AGGGTTAGGG3’ GGGTTAGGG---------
3’---AATCCCAATCCCAATCCCAATCCCAATCCC---------
17
221 S16