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Repair Systems

Repair Systems. Chapter 20. 20.1 Introduction. Figure 20.1. 20.2 Repair Systems Correct Damage to DNA. Repair systems recognize DNA sequences that do not conform to standard base pairs. Excision systems remove one strand of DNA at the site of damage and then replace it. Figure 20.2.

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Repair Systems

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  1. Repair Systems Chapter 20

  2. 20.1 Introduction Figure 20.1

  3. 20.2 Repair Systems Correct Damage to DNA • Repair systems recognize DNA sequences that do not conform to standard base pairs. • Excision systems remove one strand of DNA at the site of damage and then replace it. Figure 20.2

  4. Recombination-repair systems use recombination to replace the double-stranded region that has been damaged. • All these systems are prone to introducing errors during the repair process. • Photoreactivation is a nonmutagenic repair system that acts specifically on pyrimidine dimers. Figure 20.5

  5. 20.3 Excision Repair Systems in E. coli • The Uvr system: • makes incisions ∼12 bases apart on both sides of damaged DNA • removes the DNA between them • resynthesizes new DNA Figure 20.9

  6. 20.4 Excision-Repair Pathways in Mammalian Cells • Mammalian excision repair is triggered by directly removing a damaged base from DNA. Figure 20.10

  7. Base removal triggers the removal and replacement of a stretch of polynucleotides. • The nature of the base removal reaction determines which of two pathways for excision repair is activated. • The polδ/ε pathway replaces a long polynucleotide stretch; • the polβ pathway replaces a short stretch. Figure 20.12

  8. 20.5 Base Flipping Is Used by Methylases and Glycosylases • Uracil and alkylated bases are recognized by glycosylases and removed directly from DNA. • Pyrimidine dimers are reversed by breaking the covalent bonds between them. • Methylases add a methyl group to cytosine.

  9. All these types of enzyme act by flipping the base out of the double helix where, depending on the reaction, it is either : • removed • modified and returned to the helix Figure 20.13

  10. 20.6 Error-Prone Repair and Mutator Phenotypes • Damaged DNA that has not been repaired causes DNA polymerase III to stall during replication. • DNA polymerase V (coded by umuCD) or DNA polymerase IV (coded by dinB) can synthesize a complement to the damaged strand.

  11. The DNA synthesized by the repair DNA polymerase often has errors in its sequence. • Proteins that affect the fidelity of replication may be identified by mutator genes. • In these, mutation causes an increased rate of spontaneous mutation.

  12. 20.7 Controlling the Direction of Mismatch Repair • The mut genes code for a mismatch-repair system that deals with mismatched base pairs. Figure 20.14

  13. There is a bias in the selection of which strand to replace at mismatches. • The strand lacking methylation at a hemimethylated GATC/CTAG is usually replaced. • This repair system is used to remove errors in a newly synthesized strand of DNA. • At G-T and C-T mismatches, the T is preferentially removed. Figure 20.15

  14. 20.8 Recombination-Repair Systems in E. coli • The rec genes of E. coli code for the principal retrieval system. • The principal retrieval system functions when replication leaves a gap in a newly synthesized strand that is opposite a damaged sequence.

  15. The single strand of another duplex is used to replace the gap. • The damaged sequence is then removed and resynthesized. Figure 20.18

  16. 20.9 Recombination Is an Important Mechanism to Recover from Replication Errors • A replication fork may stall when it encounters a damaged site or a nick in DNA. • A stalled fork may reverse by pairing between the two newly synthesized strands. • A stalled fork may: • restart after repairing the damage • use a helicase to move the fork forward Figure 20.19

  17. The structure of the stalled fork is the same as a Holliday junction. • It may be converted to a duplex and DSB by resolvases. Figure 20.20

  18. 20.10 RecA Triggers the SOS System • Damage to DNA causes RecA to trigger the SOS response. • This consists of genes coding for many repair enzymes.

  19. RecA activates the autocleavage activity of LexA. • LexA represses the SOS system; its autocleavage activates those genes. Figure 20.22

  20. 20.11 Eukaryotic Cells Have Conserved Repair Systems • The yeast RAD mutations, identified by radiation sensitive phenotypes, are in genes that code for repair systems. • Xeroderma pigmentosum (XP) is a human disease caused by mutations in any one of several repair genes.

  21. A complex of proteins provides a human excision-repair mechanism. • The complex includes: • XP products • the transcription factor TFIIH • Transcriptionally active genes are preferentially repaired. Figure 20.23

  22. 20.12 A Common System Repairs Double-Strand Breaks • The NHEJ pathway can ligate blunt ends of duplex DNA. • Mutations in the NHEJ pathway cause human diseases. Figure 20.24

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