Replication 4

The End Replication Problem: Telomeres shorten with each S phase Ori DNA replication is bidirectional Polymerases move 5' to 3' Requires a labile primer 3' 5' 3' 5' 3' 5' Each round of DNA replication leaves bp DNA unreplicated at the 3' end

Telomere Structure

Telomeres 'cap' chromosome ends

The structure of mammalian telomeres

Telomere Length (humans) Number of Doublings 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 kb (germ line) to 3-5 kb after doublings (average lengths of TRFs) Replicative senescence is triggered when cells acquire one or a few critically short telomeres.

Telomerase prevents telomere shortening 3' 5' DNA Replication Telomerase DNA Polymerase Telomere shortening: telomeric chromosome fusions chromosome instability replicative senescence cell death Telomere length maintenance: essential for replicative immortality

Synthesis of telomeric sequences 1) Recognition 2) Elongation 3) Translocation DNA substrate binding to hTERT and RNA template Addition of nucleotides DNA substrate and enzyme repositioning CAAUCCCAAUC 3’ 5’ hTERT hTR 5’- GGTTAGGGTTAGGGTTAG 3’- CCAAT GGTTAGGGTTAGGGTTAG 4) Repeated translocation and elongation=repeat addition processivity

Telomere length (humans) Number of Doubling Cellular (Replicative) Senescence Normal Somatic Cells (Telomerase Negative) Germ Cells (Telomerase Positive) + Telomerase Telomere Length and Cell Division Potential

Telomere related disease werner syndrome