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20 Cards in this Set
- Front
- Back
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_____ mutations/person/day
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2 X 10 ^ 18
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Damage via
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CARCINOGENS
RADIATION METABOLISM |
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Intrinsic risk
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replication
division |
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carcinogens
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mutagens
e.g alfatoxin B1 - v.potent |
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The Ames Test (1970)
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homogenized rat liver + test compound
---> activated compound + Salmonella bacteria unable to grow ohne His --> Count colonies that can grow ohne His |
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DNA reactive group
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P
N O |
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Heterocyclic Amines
(HCA) |
from cooking red meat at high temp
procarcinogens -> form DNA adducts |
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Polycyclic Aromatic Hydrocarbons
(PAHs) |
from tobacco smoke etc)
procarcinogens -> form DNA adducts |
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Cytochrome P450 (Crp) enzymes can
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detoxify carcinogens via oxidation
*convert chemically inert procarcinogens (HCAs & PAHs) into CARCINOGENS -->DNA adducts |
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UV
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causes covalent cross-links between pyrimidine bases
e.g Cyclobutane pyrimidine dimer (CPD) Pyrimidine (6-4) pyrimidinone (6-4 PP) |
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ROS
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add O at bases
e.g dG ---> 8-oxo-dG AFFECTS BASE RECOGNITION in REPLICATION |
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Spontaneous Changes
e.g Base deamination |
causes point mutations
C->Uracil (binds A) A->hypoxanthine (binds C) G->xanathine (binds T) 5' methylcytosine->T (binds A) |
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Base deamination
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loss of NH2 groups protruding from C,A,G
C->T A->G G->A |
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at G1 checkpoint
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DNA damage
---> ATM (& ATR) ---> Chk2 (&Chk1) & p53-P --->p53-P ---> increased p21 trx ----/ cdk2:cycE ---> G1/S cell cycle arrest ----> APOPTOSIS / DNA REPAIR |
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at S checkpoint
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DNA damage
---->ATR ----> Chk1 ----> cdc25A-P ----> cdc25A-Ub ----> proteosomal degredation of cdc25A ---/ cdk2:cycE/A thus ---/cdc45 which usually recruite DNA pol for replication |
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at G2/M checkpoint
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DNA damage
--->ATM --->Chk2 --->cdc25A, 14-3-3 ---/CDK1:cycB ATR ----->chk1 ----->Wee1 -----/ CDK1:cycB |
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Base excision repair (BER)
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repairs endogenous damage (ROS, spontaneous)
DNA GLYCOSYLASE recogises and cleaves altered base creates apurinic/apyrimidinic site Apurinic/Apyrimidinic Endonuclease (APE) cleaves deoxyribosylphosphate gap is filled by polymerase ß and sealed by DNA ligase |
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Nt Excision Repair (NER)
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repairs damage from UV, Xrays, genotoxic chemicals
XPC+R23 recognise distortion and chemically altered bases ----> cleavage of 5' 24nt & 3' 5nt around error Gap filled by pol delta/epsilon + PCNA + RIPA + RFC sealed by DNA ligase > 20 protein subunits involved |
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Glutathione - S - Transferase (GST)
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REDUCING AGENT via SH group
catalyses transfer of Glutathione to reactive compounds 90% of prostate cancers have lost GST |
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Cancer susceptibility syndromes
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Li Fraumeni - loss of Chk2, p53
Ataxia Telangectasia - loss of ATM, ATR Hereditary breast cancer - BRCA1,2 HNP colon cancer - loss of 5 MMR genes Xeroderma Pigmentosum 0 loss of 7 NER genes |
