Age, Cancer and the Repair of Broken Chromosomes

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Age, Cancer and the Repair of Broken Chromosomes

• An example of basic cancer research

Thomas Caspari North West Cancer Research Fund
Institute University of Wales Bangor
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Do different cancer types share common features?
Source Cancer Research UK
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Do different cancer types share common features?

• Yes
• Cancer frequency increases with age
• Genetic instability is an early sign of
  tumorigenesis
• functional link?

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Advancing Age is the most potent Carcinogen
1 35
64
Source Cancer Research UK
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Accumulation of chromosomal breaks in early
lesions of urinary bladder, breast, lung and bowel
Bartkova et al., 2005, Nature 434, 864-870
Normal early invasive
carcinoma
? Aberrant DNA Replication
P
Chk2
DNA Double Strand Breaks
P
ATM
ATM
ATM
Histone
P
ATM
P
P
P
p53
Chk2
P
p53
Histone
P
?
DNA Repair Cell cycle Arrest Cell Death
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? Aberrant DNA Replication

• Ataxia telangiectasia mutated
• cancer-prone
• premature aging

DNA Double Strand Breaks
P
ATM
ATM
ATM
Histone
P
P
Chk2
P
p53
DNA Repair Cell cycle Arrest Cell Death
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Working Model
Normal cell signalling
Malignant cell signalling
Aberrant S phase Breaks
Activated Maintenance Systems
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Model organism - Fission yeast (Schizosaccharomyce
s pombe)
G1
cyclin
CDK
G2
P. Nurse
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A Mutation in cyclin B affects repair of broken
chromosomes
Wild type yeast
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Cyclin B activity is required for the repair of
broken chromosomes
ATM
Histone
ATM
ATM
P
ATR
-
ATRIP
ssDNA
BLM / Werner RecQ DNA Helicases
Premature Aging Cancer !!
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Amended Working Model
Normal cell signalling
Malignant cell signalling
Aberrant S phase Breaks
Abnormal Repair!!
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Driving an old car too fast..
High Levels of Cell Cycle Regulators (Cyclin E)
drive aberrant DNA replication
Bartkova et al., 2005, Nature 434, 864-870
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. till it crashes
Gorgoulis et al., 2005, Nature 434, 908-913
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The Cell Cycle DNA Repair Groupat the NWCRF
Institute in Bangor
Claire Lancaster Katarzyna
Ewert-Krzemieniewska
Special Thanks to Toni Carrs Group in Brighton