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UNIT 4 
DNA repair
INTRODUCTION 
 DNA damage occur during replication 
 Can be caused by environmental agents such as radiations, chemicals etc. 
 DNA repair systm is not that much efficient 
 If it was perfect no evolution would have happened 
 Three mechanisms alter DNA structure 
i) base substitutions during replication 
ii) base change due to chemical insteability of bases 
iii) action of other chemicals and environmental factors
EFFECTS OF THE MECHANISMS 
 Mismatch - deamination of cytosine to uracil 
 Depurination – N – Glycosidic bond spontaneously broken down at 
physiological temperature 
- 1 purine per 300 purine is removed 
 UV induced dimer formation – T-T 
 SS breaks – phosphodiester bond break by peroxides 
 DS breaks 
 Cross linking – antibiotics (mitomycine C) or reagents like nitrite ion form 
covalent linkages base in one strand and base in other strand
MISMATCH 
06_23_DEPURINATION.JPG
06_25_MUTATIONS.JPG
TYPES OF DNA DAMAGE SUMMARISED 
G A T C 
ds DNA Break Mismatch 
Thymidine dimer 
AP site 
Covalent X-linking 
ss Break 
C-U deamination
MECHANISMS OF REPAIR 
 2 major classes 
i) light induced repair 
ii) light independent pathways 
 Photoreactivation involved in the first class 
 Latter consists of 
i) excision repair 
ii) recombination repair 
iii) SOS repair 
iv) Mismatch repair
PHOTOREACTIVATION 
 Enzymatic cleavage of thymine dimers 
 Activated by visible light ( 300 - 600nm ) 
 PR enzyme / photolyase 
 1st enzyme binds to T-T specifically 
 When light absorbed T-T will be monomerised 
 Photlyase releases when repair completed
EXCISION REPAIR 
 Multi step enzymatic process 
 2 mechanisms 
a) Incision step 
b) Breakage of N- glycosidic bond of T-T 
 INCISION STEP 
 In E.coli repair endonuclease recognises distortion produced by T-T 
 Makes 2 cuts in sugar-phosphate back bone 
 1st at 8 bp to 5’ and 2nd one at 4-5 bp to 3’ 
 5’ incision produce a 3’ OH
 Pol I use that 3’ OH as primer to synthesise new strand 
 This new strand will replace the dimer containing strand 
 Joining of newly synthesised strand to original strand by ligase 
 Excised strand will be degraded to single nucleotides by the scavenging exo 
and endo nucleases 
 BREAKAGE OF N- GLYCOSIDIC BOND OF T-T 
 1st step - enzymatic cleavage of N- glycosidic bond in the 5’ thymine 
nucleotide of dimer 
 2nd step is the endonuclease activity of the same glycosylase enzyme to 
recognize a deoxyribose lacking a base 
 Make a single cut at 5’ of T-T
 Causes formation of 3’ OH 
 Since it is on a base pair free deoxyribose it can not be used to prime DNA 
synthesis 
 In an unknown way deoxyribose will be removed and Pol I act at the new 3’ 
OH 
 Strand displacement in an excision step by Pol I 
 Filling the gap 
 Mammalian mechanism is poorly understood 
 In E.coli incision is determined by products of the following genes 
a)uvrA 
b)uvrB 
c)uvrC 
 Role of uvr gene product can be determinde by the mutants 
 xeroderma pigmentosum in human is due to inability to carry out excision repair
RECOMBINATION REPAIR 
 Thymine dimers are produced in large numbers so that it can not be completely 
removed by excision repair 
 Another mechanism for uv induced thymine dimer removal is the recombination 
repair 
 recA gene is involved 
 During replication thymine dimer causes distortion 
 Adenine will be added and removed continously 
 DNA synthesis restarts in 2 ways in such cases 
i) postdimer initiation 
ii) transdimer synthesis 
 Postdimer initiation is responsible for recombination repair 
 Transdimer synthesis results in SOS repair
 Thymine dimer will be excised but gap will not be filled 
 So daughter strand will be a fragmented one 
 It can overcome by a recombination mechanism called sister – strand 
exchange 
 Good strand from a homologous DNA is excised and used to fill the gap 
 DNA Pol I and ligase involved in the process 
 As the strand is not synthesised newly to remove the gap it is less time 
consuming and hence much important 
 As it occur after replication it is called as postreplicational repair 
 Another name daughter strand gap repair
SOS REPAIR 
 Global response to DNA damage in which the cell cycle is arrested and 
DNA repair and mutagenesis are induced 
 Functional recA gene is needed 
 RecA protein binds to the SS DNA 
 Binds at distortions 
 RecA binds with the ε part of polymerase which is involved in the editing and 
inhibits editing function- mutations will persist in daughter strand 
 Other 2 genes involved are umuC and umuD 
 Their function is not known 
 3 hypothesis are there 
1) facilitate binding of RecA to the small distortions 
2) facilitate binding of polymerase to the distortions 
3) enable release of polymerase
 During normal growth, the SOS genes are negatively regulated by LexA 
repressor protein dimers 
 During a normal cell’s life, the SOS system is turned off, because lexA 
represses expression of all the critical proteins. 
 However, when DNA damage occurs, RecA binds to single-stranded DNA 
(single-stranded when a lesion creates a gap in daughter DNA). As DNA 
damage accumulates, more RecA will be bound to the DNA to repair the 
damage. 
 RecA, in addition to its abilities in recombination repair, stimulates the 
autoproteolysis of lexA’s gene product .That is, LexA will cleave itself in 
the presence of bound RecA, which causes cellular levels of LexA to drop, 
which, in turn, causes coordinate derepression (induction) of the SOS 
regulon genes.
 As damage is repaired, RecA releases DNA; in this 
unbound form, it no longer causes the autoproteolysis of 
LexA, and so the cellular levels of LexA rise to normal 
again, shutting down expression of the SOS regulon 
genes. 
 Activation of the SOS genes occurs after DNA damage 
by the accumulation of ssDNA regions generated at 
replication forks, where DNA polymerase is blocked.
Gene Repair Function 
lexA SOS repressor 
recA 
SOS regulator; SOS mutagenesis; recF-dependent recombinational repair; recB-dependent repair of double-strand 
gaps; cross-link repair 
recN recF-dependent recombinational repair; repair of double-strand gaps 
recQ recF-dependent recombinational repair 
ruv recF-dependent recombinational repair 
umuC SOS mutagenesis (Error prone repair) 
umuD SOS mutagenesis (Error prone repair) 
uvrA Short-patch nucleotide-excision repair; long-patch nucleotide-excision repair; cross-link repair 
uvrB Short-patch nucleotide-excision repair; long-patch nucleotide-excision repair; cross-link repair 
uvrD 
Short-patch nucleotide-excision repair; recF-dependent recombinational repair; recB-dependent repair of double-strand 
gaps; cross-link repair; methylation-directed mismatch repair 
dinA SOS mutagenesis (?) 
sulA Inhibitor of cell division 
List of some SOS 
regulon genes in E. coli
MISMATCH REPAIR 
 Highly conserved biological pathway 
 Important in maintaining genome stability 
 It is mainly to repair base- base mismatches and insertion/deletion of 
bases during replication and recombination 
 Inactive mismatch repair will cause spontaneous mutation 
 Mismatch repair prevent mutagenesis and tumorogenesis 
 E.coli MutS and MutL and their eukaryotic homologs, MutSα 
and MutLα, respectively, are key players in MMR-associated 
genome maintenance
 In E.coli Proteins involved are 
1) MutS, MutL, MutH, DNA helicase II (MutU/UvrD), 
2) four exonucleases (ExoI, ExoVII, ExoX, and RecJ) 
3) singlestranded DNA binding protein (SSB) 
4) DNA polymerase III holoenzyme 
5)DNA ligase 
 MutS recognizes base-base mismatches 
 MutL interacts physically with MutS, enhances mismatch 
recognition, and recruits and activates MutH 
 MutH, an enzyme that causes an incision or nick on one 
strand near the site of the mismatch
 action of a specific helicase(UvrD) and one of three exonucleases. 
 The helicase unwinds the DNA ,starting from the incision and moving 
in the direction of the site of the mismatch ,and the exonuclease 
progressively digests the displaced nucleotide. 
 This action produces a single-strand gap, which is then filled in by 
DNA polymeraseⅢ and sealed with DNA ligase. 
 Dam methylases tags the parental strand by transient 
hemimethylation and methylates A residues on both strands of the 
sequence 5’-GATC-3’. 
 MutH protein become activated only when it is contacted by MutL 
and MutS located at a nearby mismatch 
 In human proteins are 
1) MutSα and MutLα 
2)PCNA and RPA 
 human MutS and MutL homologues are heterodimers 
 hMutSα preferentially recognizes base-base mismatches
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dna repair

  • 1. UNIT 4 DNA repair
  • 2. INTRODUCTION  DNA damage occur during replication  Can be caused by environmental agents such as radiations, chemicals etc.  DNA repair systm is not that much efficient  If it was perfect no evolution would have happened  Three mechanisms alter DNA structure i) base substitutions during replication ii) base change due to chemical insteability of bases iii) action of other chemicals and environmental factors
  • 3. EFFECTS OF THE MECHANISMS  Mismatch - deamination of cytosine to uracil  Depurination – N – Glycosidic bond spontaneously broken down at physiological temperature - 1 purine per 300 purine is removed  UV induced dimer formation – T-T  SS breaks – phosphodiester bond break by peroxides  DS breaks  Cross linking – antibiotics (mitomycine C) or reagents like nitrite ion form covalent linkages base in one strand and base in other strand
  • 6. TYPES OF DNA DAMAGE SUMMARISED G A T C ds DNA Break Mismatch Thymidine dimer AP site Covalent X-linking ss Break C-U deamination
  • 7. MECHANISMS OF REPAIR  2 major classes i) light induced repair ii) light independent pathways  Photoreactivation involved in the first class  Latter consists of i) excision repair ii) recombination repair iii) SOS repair iv) Mismatch repair
  • 8. PHOTOREACTIVATION  Enzymatic cleavage of thymine dimers  Activated by visible light ( 300 - 600nm )  PR enzyme / photolyase  1st enzyme binds to T-T specifically  When light absorbed T-T will be monomerised  Photlyase releases when repair completed
  • 9. EXCISION REPAIR  Multi step enzymatic process  2 mechanisms a) Incision step b) Breakage of N- glycosidic bond of T-T  INCISION STEP  In E.coli repair endonuclease recognises distortion produced by T-T  Makes 2 cuts in sugar-phosphate back bone  1st at 8 bp to 5’ and 2nd one at 4-5 bp to 3’  5’ incision produce a 3’ OH
  • 10.  Pol I use that 3’ OH as primer to synthesise new strand  This new strand will replace the dimer containing strand  Joining of newly synthesised strand to original strand by ligase  Excised strand will be degraded to single nucleotides by the scavenging exo and endo nucleases  BREAKAGE OF N- GLYCOSIDIC BOND OF T-T  1st step - enzymatic cleavage of N- glycosidic bond in the 5’ thymine nucleotide of dimer  2nd step is the endonuclease activity of the same glycosylase enzyme to recognize a deoxyribose lacking a base  Make a single cut at 5’ of T-T
  • 11.  Causes formation of 3’ OH  Since it is on a base pair free deoxyribose it can not be used to prime DNA synthesis  In an unknown way deoxyribose will be removed and Pol I act at the new 3’ OH  Strand displacement in an excision step by Pol I  Filling the gap  Mammalian mechanism is poorly understood  In E.coli incision is determined by products of the following genes a)uvrA b)uvrB c)uvrC  Role of uvr gene product can be determinde by the mutants  xeroderma pigmentosum in human is due to inability to carry out excision repair
  • 12.
  • 13. RECOMBINATION REPAIR  Thymine dimers are produced in large numbers so that it can not be completely removed by excision repair  Another mechanism for uv induced thymine dimer removal is the recombination repair  recA gene is involved  During replication thymine dimer causes distortion  Adenine will be added and removed continously  DNA synthesis restarts in 2 ways in such cases i) postdimer initiation ii) transdimer synthesis  Postdimer initiation is responsible for recombination repair  Transdimer synthesis results in SOS repair
  • 14.  Thymine dimer will be excised but gap will not be filled  So daughter strand will be a fragmented one  It can overcome by a recombination mechanism called sister – strand exchange  Good strand from a homologous DNA is excised and used to fill the gap  DNA Pol I and ligase involved in the process  As the strand is not synthesised newly to remove the gap it is less time consuming and hence much important  As it occur after replication it is called as postreplicational repair  Another name daughter strand gap repair
  • 15.
  • 16. SOS REPAIR  Global response to DNA damage in which the cell cycle is arrested and DNA repair and mutagenesis are induced  Functional recA gene is needed  RecA protein binds to the SS DNA  Binds at distortions  RecA binds with the ε part of polymerase which is involved in the editing and inhibits editing function- mutations will persist in daughter strand  Other 2 genes involved are umuC and umuD  Their function is not known  3 hypothesis are there 1) facilitate binding of RecA to the small distortions 2) facilitate binding of polymerase to the distortions 3) enable release of polymerase
  • 17.  During normal growth, the SOS genes are negatively regulated by LexA repressor protein dimers  During a normal cell’s life, the SOS system is turned off, because lexA represses expression of all the critical proteins.  However, when DNA damage occurs, RecA binds to single-stranded DNA (single-stranded when a lesion creates a gap in daughter DNA). As DNA damage accumulates, more RecA will be bound to the DNA to repair the damage.  RecA, in addition to its abilities in recombination repair, stimulates the autoproteolysis of lexA’s gene product .That is, LexA will cleave itself in the presence of bound RecA, which causes cellular levels of LexA to drop, which, in turn, causes coordinate derepression (induction) of the SOS regulon genes.
  • 18.  As damage is repaired, RecA releases DNA; in this unbound form, it no longer causes the autoproteolysis of LexA, and so the cellular levels of LexA rise to normal again, shutting down expression of the SOS regulon genes.  Activation of the SOS genes occurs after DNA damage by the accumulation of ssDNA regions generated at replication forks, where DNA polymerase is blocked.
  • 19.
  • 20. Gene Repair Function lexA SOS repressor recA SOS regulator; SOS mutagenesis; recF-dependent recombinational repair; recB-dependent repair of double-strand gaps; cross-link repair recN recF-dependent recombinational repair; repair of double-strand gaps recQ recF-dependent recombinational repair ruv recF-dependent recombinational repair umuC SOS mutagenesis (Error prone repair) umuD SOS mutagenesis (Error prone repair) uvrA Short-patch nucleotide-excision repair; long-patch nucleotide-excision repair; cross-link repair uvrB Short-patch nucleotide-excision repair; long-patch nucleotide-excision repair; cross-link repair uvrD Short-patch nucleotide-excision repair; recF-dependent recombinational repair; recB-dependent repair of double-strand gaps; cross-link repair; methylation-directed mismatch repair dinA SOS mutagenesis (?) sulA Inhibitor of cell division List of some SOS regulon genes in E. coli
  • 21. MISMATCH REPAIR  Highly conserved biological pathway  Important in maintaining genome stability  It is mainly to repair base- base mismatches and insertion/deletion of bases during replication and recombination  Inactive mismatch repair will cause spontaneous mutation  Mismatch repair prevent mutagenesis and tumorogenesis  E.coli MutS and MutL and their eukaryotic homologs, MutSα and MutLα, respectively, are key players in MMR-associated genome maintenance
  • 22.  In E.coli Proteins involved are 1) MutS, MutL, MutH, DNA helicase II (MutU/UvrD), 2) four exonucleases (ExoI, ExoVII, ExoX, and RecJ) 3) singlestranded DNA binding protein (SSB) 4) DNA polymerase III holoenzyme 5)DNA ligase  MutS recognizes base-base mismatches  MutL interacts physically with MutS, enhances mismatch recognition, and recruits and activates MutH  MutH, an enzyme that causes an incision or nick on one strand near the site of the mismatch
  • 23.  action of a specific helicase(UvrD) and one of three exonucleases.  The helicase unwinds the DNA ,starting from the incision and moving in the direction of the site of the mismatch ,and the exonuclease progressively digests the displaced nucleotide.  This action produces a single-strand gap, which is then filled in by DNA polymeraseⅢ and sealed with DNA ligase.  Dam methylases tags the parental strand by transient hemimethylation and methylates A residues on both strands of the sequence 5’-GATC-3’.  MutH protein become activated only when it is contacted by MutL and MutS located at a nearby mismatch  In human proteins are 1) MutSα and MutLα 2)PCNA and RPA  human MutS and MutL homologues are heterodimers  hMutSα preferentially recognizes base-base mismatches