6.Repair_lect09

6.Repair_lect09 - Determinants of DNA replication fidelity...

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Unformatted text preview: Determinants of DNA replication fidelity Post-Replication DNA Mismatch Repair Replication Primary chain elongation: Polymerase selectivity Exonucleolytic Proofreading Pre-Replication Sanitizing dNTP Pools (e.g., dUTP, 8-O-dGTP) Base Excision Repair Nucleotide Excision Repair Interstrand Crosslink Repair ssDNA Break Repair Non-Homologous End Joining 5' 3' X X 5' 5' Specialized reactions: Translesion synthesis Recombinational Repair Replication Associated Repair (e.g., of incorporated dUMP) Sister Chromatid Cohesion Signal apoptosis after damage Meiotic recombination Stop homeologous recomb. Transcription-coupled repair Control gene amplification SHM of Ig genes 3’ DNA Polymerase Gene (Alias) Polymerase Family Chromosomal Location Associated Activities α (alpha) POLA B Xp21.3-22.1 RNA primas e β (beta) POLB X 8p11-12 dRP lyase and AP lyase γ (gamma) POLG A 15q24 3´to 5´ exo, dRP lyas e δ (delta) POLD1 B 19q13.3-13.4 3´to 5´ exo ε (epsilon) POLE B 12q24.3 3´to 5´ exo ζ (zeta) POLZ (REV3) B 6q21-22.2 η (eta) POLH (XPV, RAD30A) Y 6p21.1 θ (theta) POLQ A 3q13.3 ι (iota) POLI (RAD30B) Y 18q21.1 dRP lyase κ (kappa) POLK (DINB1) Y 5q13 λ (lambda) POLL X 10q24.3-25.1 dRP lyase μ (mu) POLM X 7p13 terminal transferase σ (sigma) POLS (TRF4-1) X 5p15 3´to 5´ exo Rev1 REV1 Y 2q11 deoxycytidine transferase DNA Template Dependent Human DNA Polymerases Replication of undamaged DNA: DNA synthesis: Pol α " ½ δ Pol ε Pol γ η å ↔ Pol σ ? Proofreading: Pol δ Pol ε Pol γ η å ↔ 5' 3' 3' 5' Damage Mismatch Mismatch repair: General: Pol δ ? Pol ε ? Specialized (G • U mispairs): Pol β Lesion bypass: Pol ζ Pol η ª * κ REV1 Pol ι ? S-phase checkpoint: Pol ε Pol α Functions of DNA Polymerases during and after Replication How mismatches are produced? Mismatch---base-base mispair---Insertion-deletion loops (IDLs) Average :Error rate of DNA polymerase: 1 in 10 5-10 7 average Human genome: 3.15 × 10 9 Recombination physical damage to DNA or to nucleotide precursors ( e. g . deamination of 5-methylcytosine) (1) (2) (3) DNA MMR and cancer • Post-replication DNA MMR can decrease the mutation rate by 3 orders of magnitude • In human, mutations in MMR genes have been linked to hereditary non-polyposis colorectal cancer (HNPCC) and several sporadic cancers Multi-step checking by high fidelity DNA pol • Base-base geometry, induced fit • a hydrophobic base binding pocket • Kinetic trapping of mismatches for proofreading • Melting the mismatched base pair for proofreading Kunkel and Bebenek, 2000, Annu Rev Biochem, vol 69, 497-529 The task that is left by DNA pol • Average error rate: 1 in 10 5-10 7 • Error frequency most common: G/T least common: pyrimidine-pyrimidine • Sequence context More often in G/C rich environment than in A/T rich Echols and Goodman, 1991, Annu Rev Biochem, vol 60, 477- 511 How does DNA MMR work?How does DNA MMR work?...
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This note was uploaded on 03/03/2010 for the course CHEM 431 taught by Professor Pielak during the Spring '07 term at UNC.

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6.Repair_lect09 - Determinants of DNA replication fidelity...

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