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DNA repair by:S.Solali
 
Types of DNA Damage ,[object Object],[object Object],[object Object],[object Object]
 
Types of DNA Damage (cont.) ,[object Object],[object Object],[object Object]
IMPORTANCE OF DNA REPAIR Hoeijmakers , 2001
DNA Repair ,[object Object],[object Object],[object Object]
 
 
Methyl-directed mismatch repair ,[object Object],[object Object],[object Object]
Mismatch repair ,[object Object],[object Object],[object Object],[object Object],[object Object]
Mismatch Repair in E.coli ,[object Object],[object Object],[object Object],[object Object],[object Object]
Methyl Directed MisMatch repair in E. coli
Methylataion and Mismatch Repair
Model for Mismatch Repair
 
Excision Repair •  Conserved throughout evolution, found in all prokaryotic and eukaryotic organisms •  Three step process: –  1. Error is recognized and enzymatically clipped out by a nuclease that cleaves the phosphodiester bonds (uvr gene products operate at this step) –  2. DNA Polymerase I fills in the gap by inserting the appropriate nucleotides –  3. DNA Ligase seals the gap
Excision Repair •  Two know types of excision repair –  Base excision repair (BER) •  corrects damage to nitrogenous bases created by the spontaneous hydrolysis of DNA bases as well as the hydrolysis of DNA bases caused by agents that chemically alter them –  Nucleotide excision repair (NER) •  Repairs “bulky” lesions in DNA that alter or distort the regular DNA double helix •  Group of genes (uvr) involved in recognizing and clipping out the lesions in the DNA •  Repair is completed by DNA pol I and DNA ligase
Base excision Repair ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]
Base excision repair. ,[object Object],[object Object],[object Object],[object Object],[object Object]
Mechanism 1.DNA glycosylase recognizes Specific Damaged base 2. Cleaves glycosl bond to remove Base 3. AP endonuclease cleaves  Backbone 4. DNA Pol removes abasic site 5. Replacement of Base
Base Excision Repair (BER) Variety of  DNA glycosylases , for different types of damaged bases. AP endonuclease  recognizes sites with a missing base; cleaves sugar-phosphate backbone. Deoxyribose phosphodiesterase  removes the sugar-phosphate lacking the base.   Deaminated C Fig. 6.15
Nucleotide Excision Repair ,[object Object],[object Object],[object Object],[object Object],[object Object],Ludovic C. J. Gillet and Orlando D. Scharer  Molecular Mechanisms of Mammalian Global Genome Nucleotide Excision Repair  Chem. Rev.  2006,  106, 253-276
Excision repair In this form of repair the gene products of the E. coli  uvrA ,  uvrB  and  uvrC  genes form an enzyme complex that  physically cuts out (excises the damged strand containing the pyrimidine dimers. An incision is made 8 nucleotides (nt) away for the pyrimidine dimer on the 5’ side and 4 or 5 nt on the 3’ side..  The damaged strand is removed by  uvrD , a helicase and then repaired by DNA pol I and DNA ligase. Is error-free.
T T T T Damage recognised  by UvrABC, nicks  made on  both sides of dimer Dimer removed by UvrD, a helicase Gap filled by DNA pol I and the nick sealed by DNA ligase Excision Repair in  E.coli   5’ 3’ 3’ 5’ 5’ 3’ 5’ 3’ 5’ 3’ 3’ 5’ 3’ 5’ 3’ 5’ T T
Nucleotide-Excision Repair in  E. coli  and Humans
Excision repair The  UvrABC complex is referred to as an exinuclease. UvrAB proteins identify the bulky dimer lesion, UvrA protein then leaves, and UvrC protein then binds to UvrB protein and introduces the nicks on either side of the dimer. In man there is a similar process carried out by 2 related enzyme complexes: global excision repair and transcription coupled repair. Several human syndromes deficient in excision repair, Xeroderma pigmentosum, Cockayne Syndrome, and are characterised by extreme sensitivity to UV light (& skin cancers)
Nucleotide Excision Repair ,[object Object],[object Object],[object Object],[object Object],[object Object]
Nucleotide Excision Repair ,[object Object],[object Object],[object Object],[object Object]
Nucleotide Excision Repair ,[object Object],[object Object],[object Object]
Photoactivation Repair in E. coli •  Exposing UV treated cells to blue light results in a reversal of the thymine dimer formation •  Enzyme, photoactivation repair enzyme (PRE) absorbs a photon of light (from blue light) and is able to cleave the bond forming the thymine dimer. •  Once bond is cleaved, DNA is back to normal
Direct Repair: Photoreactivation by photolyase
Alkylation of DNA by alkylating agents
O 6 -methyl G, if not repaired, may produce a mutation
Direct Repair:   Reversal of O6 methyl G to G by methyltransferase
Direct re Direct repair of alkylated bases by AlkB.
 
Pairing of homologous chromosomes and crossing-over in meiosis .
Helicase and nuclease activities of the RecBCD
Helicase and nuclease activities of the RecBCD
The RecBCD pathway of recombination
Recombination during meiosisis initiated by double-strand breaks .
RuvA  and  RuvB ,[object Object],[object Object],[object Object],[object Object],[object Object]
 
RuvC  bound to Holliday junction Fig. 22.31a
Models for recombinational DNA repair
Models for recombinational DNA repair of  stalled replication fork
DNA non-homologous end-joining (NHEJ) ,[object Object],[object Object],[object Object]
Homologous recombination Resection Rad50, Mre11, Xrs2 complex Strand invasion Rad52 Rad51; BRCA2 DNA synthesis     Ligation, branch migration, Holliday junction resolution DSB Non-homologous end-joining Ku70, Ku80 Ligation DSB Rad50, Mre11, Xrs2 complex “ Cleaning up” of ends XRCC4/Ligase IV DNA-PKcs
DNA-dependent protein kinase (DNA-PK) INACTIVE ACTIVE  KINASE DNA DNA-PK DNA-PK
DNA-PK has three subunits I N A C T I V E A C T I V E D N A K u 7 0 K u 8 0 D N A - P K c s 6 9 k D a 8 3 k D a 4 7 0 k D a D N A - P K c s A T P A D P X P Target sites:  Ser/Thr-Gln K u 7 0 K u 8 0
DNA-PK has three subunits I N A C T I V E A C T I V E D N A K u 7 0 K u 8 0 D N A - P K c s 6 9 k D a 8 3 k D a 4 7 0 k D a D N A - P K c s A T P A D P X P …  and is activated by DNA DSBs! K u 7 0 K u 8 0
Multiple potential roles for Ku/DNA-PKcs in NHEJ
Fig. 20.38 Model for nonhomologous end-joining
End-joining repair of nonhomologous DNA
SOS response ,[object Object],[object Object]
The Error-Prone (SOS) Repair Mechanism The error-prone repair mechanism involves DNA pol. III and 2 other gene products encoded by  umuCD. The UmuCD proteins are produced in times of dire emergency and instruct DNA pol. III to insert  any  bases opposite the tymine dimers, as the DNA damage would otherwise be lethal. The risk of several mutations is worth the risk as measured against threat of death. How is this SOS repair activated?
The SOS response In response to extensive genetic damage there is a regulatory system that co-ordinates the bacterial cell response. This results in the increased expression of  >30 genes, involved in DNA repair, these include: recA  -  activator of SOS response, recombination sfiA (sulA)  -  a cell division inhibitor (repair before  replication) umuC ,  D    - an error prone bypass of thymine dimers (loss of fidelity in DNA replication) uvrA , B , C , D  -  excision repair The SOS response is regulated by two key genes:   recA  &  lexA
SOS ,[object Object],[object Object],[object Object],[object Object]
SOS ,[object Object],[object Object]
SOS ,[object Object],[object Object]

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DNA repair

  • 2.  
  • 3.
  • 4.  
  • 5.
  • 6. IMPORTANCE OF DNA REPAIR Hoeijmakers , 2001
  • 7.
  • 8.  
  • 9.  
  • 10.
  • 11.
  • 12.
  • 13. Methyl Directed MisMatch repair in E. coli
  • 16.  
  • 17. Excision Repair • Conserved throughout evolution, found in all prokaryotic and eukaryotic organisms • Three step process: – 1. Error is recognized and enzymatically clipped out by a nuclease that cleaves the phosphodiester bonds (uvr gene products operate at this step) – 2. DNA Polymerase I fills in the gap by inserting the appropriate nucleotides – 3. DNA Ligase seals the gap
  • 18. Excision Repair • Two know types of excision repair – Base excision repair (BER) • corrects damage to nitrogenous bases created by the spontaneous hydrolysis of DNA bases as well as the hydrolysis of DNA bases caused by agents that chemically alter them – Nucleotide excision repair (NER) • Repairs “bulky” lesions in DNA that alter or distort the regular DNA double helix • Group of genes (uvr) involved in recognizing and clipping out the lesions in the DNA • Repair is completed by DNA pol I and DNA ligase
  • 19.
  • 20.
  • 21. Mechanism 1.DNA glycosylase recognizes Specific Damaged base 2. Cleaves glycosl bond to remove Base 3. AP endonuclease cleaves Backbone 4. DNA Pol removes abasic site 5. Replacement of Base
  • 22. Base Excision Repair (BER) Variety of DNA glycosylases , for different types of damaged bases. AP endonuclease recognizes sites with a missing base; cleaves sugar-phosphate backbone. Deoxyribose phosphodiesterase removes the sugar-phosphate lacking the base. Deaminated C Fig. 6.15
  • 23.
  • 24. Excision repair In this form of repair the gene products of the E. coli uvrA , uvrB and uvrC genes form an enzyme complex that physically cuts out (excises the damged strand containing the pyrimidine dimers. An incision is made 8 nucleotides (nt) away for the pyrimidine dimer on the 5’ side and 4 or 5 nt on the 3’ side.. The damaged strand is removed by uvrD , a helicase and then repaired by DNA pol I and DNA ligase. Is error-free.
  • 25. T T T T Damage recognised by UvrABC, nicks made on both sides of dimer Dimer removed by UvrD, a helicase Gap filled by DNA pol I and the nick sealed by DNA ligase Excision Repair in E.coli 5’ 3’ 3’ 5’ 5’ 3’ 5’ 3’ 5’ 3’ 3’ 5’ 3’ 5’ 3’ 5’ T T
  • 26. Nucleotide-Excision Repair in E. coli and Humans
  • 27. Excision repair The UvrABC complex is referred to as an exinuclease. UvrAB proteins identify the bulky dimer lesion, UvrA protein then leaves, and UvrC protein then binds to UvrB protein and introduces the nicks on either side of the dimer. In man there is a similar process carried out by 2 related enzyme complexes: global excision repair and transcription coupled repair. Several human syndromes deficient in excision repair, Xeroderma pigmentosum, Cockayne Syndrome, and are characterised by extreme sensitivity to UV light (& skin cancers)
  • 28.
  • 29.
  • 30.
  • 31. Photoactivation Repair in E. coli • Exposing UV treated cells to blue light results in a reversal of the thymine dimer formation • Enzyme, photoactivation repair enzyme (PRE) absorbs a photon of light (from blue light) and is able to cleave the bond forming the thymine dimer. • Once bond is cleaved, DNA is back to normal
  • 33. Alkylation of DNA by alkylating agents
  • 34. O 6 -methyl G, if not repaired, may produce a mutation
  • 35. Direct Repair: Reversal of O6 methyl G to G by methyltransferase
  • 36. Direct re Direct repair of alkylated bases by AlkB.
  • 37.  
  • 38. Pairing of homologous chromosomes and crossing-over in meiosis .
  • 39. Helicase and nuclease activities of the RecBCD
  • 40. Helicase and nuclease activities of the RecBCD
  • 41. The RecBCD pathway of recombination
  • 42. Recombination during meiosisis initiated by double-strand breaks .
  • 43.
  • 44.  
  • 45. RuvC bound to Holliday junction Fig. 22.31a
  • 47. Models for recombinational DNA repair of stalled replication fork
  • 48.
  • 49. Homologous recombination Resection Rad50, Mre11, Xrs2 complex Strand invasion Rad52 Rad51; BRCA2 DNA synthesis     Ligation, branch migration, Holliday junction resolution DSB Non-homologous end-joining Ku70, Ku80 Ligation DSB Rad50, Mre11, Xrs2 complex “ Cleaning up” of ends XRCC4/Ligase IV DNA-PKcs
  • 50. DNA-dependent protein kinase (DNA-PK) INACTIVE ACTIVE KINASE DNA DNA-PK DNA-PK
  • 51. DNA-PK has three subunits I N A C T I V E A C T I V E D N A K u 7 0 K u 8 0 D N A - P K c s 6 9 k D a 8 3 k D a 4 7 0 k D a D N A - P K c s A T P A D P X P Target sites: Ser/Thr-Gln K u 7 0 K u 8 0
  • 52. DNA-PK has three subunits I N A C T I V E A C T I V E D N A K u 7 0 K u 8 0 D N A - P K c s 6 9 k D a 8 3 k D a 4 7 0 k D a D N A - P K c s A T P A D P X P … and is activated by DNA DSBs! K u 7 0 K u 8 0
  • 53. Multiple potential roles for Ku/DNA-PKcs in NHEJ
  • 54. Fig. 20.38 Model for nonhomologous end-joining
  • 55. End-joining repair of nonhomologous DNA
  • 56.
  • 57. The Error-Prone (SOS) Repair Mechanism The error-prone repair mechanism involves DNA pol. III and 2 other gene products encoded by umuCD. The UmuCD proteins are produced in times of dire emergency and instruct DNA pol. III to insert any bases opposite the tymine dimers, as the DNA damage would otherwise be lethal. The risk of several mutations is worth the risk as measured against threat of death. How is this SOS repair activated?
  • 58. The SOS response In response to extensive genetic damage there is a regulatory system that co-ordinates the bacterial cell response. This results in the increased expression of >30 genes, involved in DNA repair, these include: recA - activator of SOS response, recombination sfiA (sulA) - a cell division inhibitor (repair before replication) umuC , D - an error prone bypass of thymine dimers (loss of fidelity in DNA replication) uvrA , B , C , D - excision repair The SOS response is regulated by two key genes: recA & lexA
  • 59.
  • 60.
  • 61.