Lecture 12 DNA Damage_Telomerase.key

Lecture 12 DNA Damage_Telomerase.key - Lecture 12 DNA...

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Lecture 12 DNA Damage and Repair How DNA is normally repaired and the consequences of mutations in the enzymes necessary for repair p53 has been named ‘The Guardian of the Genome’ and ‘The Master Sensor of Stress’ Growth Factors p21 DNA Damage 1 2
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DNA Damage Checkpoints Cells sense DNA damage stop cell cycle progression. Different checkpoints: G1/S checkpoint and DNA repair mechanisms. G2/M checkpoint Checkpoint and DNA repair enzymes are tumor suppressors. Generic DNA damage checkpoint pathway 3 4
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Both ATM and ATR lead to p53 activation either directly or through the Chk kinases. Ser15 PO 4 p53 activity. Ser20 PO 4 prevents MDM2 binding. ATM inactivates MDM2 by PO 4 . ATM/ATR activation by DNA damage = high p53 activity. DNA DAMAGE ATM and ATR are activated by distinct forms of DNA Damage (DSBs) ATM is activated mostly by double stranded-breaks ATR is activated mostly by stalled replication forks 5 6
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ATM and ATR are recruited by different ‘sensor’ proteins (DSBs) ATM is recruited by the NRM complex: NBS1, RAD50 and MRE11. ATR is recruited by the 9-1-1 complex: Rad9, Rad1, Hus1 Checkpoint kinases amplify the signal and stop the cell cycle by phosphorylating key components of the cell cycle machinery Checkpoint kinases 7 8
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Components of the ATM pathway are tumor suppressor genes A taxia T elangiectasia M utated Radiation Sensitivity Mutants AT M R elated Gene N ijmegen B reakage S yndrome Ataxia Telangiectasia extreme cellular sensitivity to radiation. The patients suffer cancer predisposition and neurodegeneration NBS is a chromosomal-instability syndrome similar to A-T, with cancer predisposition, radiosensitivity, microcephaly, and growth retardation. Components of the ATR pathway are also tumor suppressors AT M R elated Gene N ijmegen B reakage S yndrome Although BRCA1 mutations present in 1-2% of breast cancers, mutations in BRCA1 and BRCA2 account for to 84% of hereditary breast cancer cases. BRCA1 complexes with
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This note was uploaded on 03/06/2010 for the course MCDB 3150 taught by Professor Staff during the Spring '08 term at Colorado.

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Lecture 12 DNA Damage_Telomerase.key - Lecture 12 DNA...

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