chapter9themutabilityandrepairofdna(存儲版)
【正文】 n or by aberrant action of cellular rebination processes. Rate of spontaneous mutation at any given site on chromosomal ranges from 106 to 1011 per round of DNA replication, with some sites being “ hotspot” . Mutationprone sequence in human genome are repeats of simple di, tri or tetranucleotide sequences, known as DNA microsatellites (微衛(wèi)星 DNA). These sequences (1) are important in human geics and disease, (2) hard to be copied accurately and highly polymorphic in the population. the replication errors are resulted? Each bases has its preferred tautomeric form (Ch 6) The strictness of the rules for “ WastonCrick” pairing derives from the plementarity both of shape and of hydrogen bonding properties between adenine and thymine and between guanine and cytosine. Some replication errors escape proofreading The 3’ 5’ exonuclease activity of replisome only improves the fidelity of DNA replication by a factor of 100fold. The misincorporated nucleotide needs to be detected and replaced, otherwise it will cause mutation (Fig. 92). Replication errors and replication Figure 92 Generation of Mutation 2. How the replication errors are repaired? Mismatch repair removes errors that escape proofreading Increase the accuracy of DNA synthesis for 23 orders of magnitudes. Two challenges: (1)rapidly find the mismatches/mispairs, (2) Accurately correct the mismatch Replication errors and replication Talking about the story of E. coli repair system MutS scans the DNA, recognizing the mismatch from the distortion they cause in the DNA backbone MutS embraces the mismatchcontaining DNA, inducing a pronounced kink in the DNA and a conformational change in MutS itself Figure 94 Crystal structure of MutS MutS is a dimer. One monomer interacts with the mismatch specifically, and the other nonspecifically. DNA is kinked MutSmismatchcontaining DNA plex recruits MutL, MutL activates MutH, an enzyme causing an incision or nick on one strand near the site of the mismatch. Nicking is followed by the specific helicase (why?) (UrvD) and one of three exonucleases (why?). DNA polymerase III Helicase Exonuclease, Detail 1: How does the E. coli mismatch repair system know which of the two mismatched nucleotide to replace? The newly synthesized strand is not methylated by Dam methylase in a few minutes after the synthesis. Figure 95 Detail 2: Different exonucleases are used to r
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