Mismatch excision repair

Mismatched base pairs can arise from errors that occur during recombination repair. A variety of prokaryotic and eukaryotic mismatch repair proteins repair mismatched base pairs by a variety of mechanisms that involve the excision of one of the bases [69, 70]. 

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Loss of Mismatch Excision Repair Leads to Colon and Other Cancers... 

Figure 36-24. Nucleotide excision-repair. This mechanism is employed to correct larger defects in DNA and generally involves more proteins than either mismatch or base excision-repair. After defect recognition (indicated by XXXX) and unwinding of the DNA encompassing the defect, an excision nuclease (exinucle-ase) cuts the DNA upstream and downstream of the defective region. This gap is then filled in by a polymerase (5/e in humans) and religated.

Utilising a reversion assay in Salmonella enterica, Prieto et al reported an increased frequency of point mutations following bile-salt exposure. Mutations were predominantly nucleotide substitutions (GC to AT transitions) and -1 frameshift mutations.The frameshifts were dependent on SOS induction and linked to the activity of DinB polymerase (Pol IV). The authors proposed that the GC to AT transitions stimulated by bile, could have arisen from oxidative processes giving rise to oxidised cytosine residues. Consistent with this hypothesis, the authors demonstrated that strains of S. enterica-lacking enzymes required for base-excision repair (endonuclease III and exonuclease IV) and the removal of oxidised bases, demonstrated increased bile-acid sensitivity compared with competent strains. In another study using E. coli, resistance to the DNA-damaging effects of bile was associated with Dam-directed mismatch repair, a pathway also involved with the repair of oxidative DNA lesions. ... 

Fig. 1. Proteins in DNA repair pathways. DNA repair proteins are listed for each of the following pathways BER (Base Excision Repair), NER (Nucleotide Excision Repair), MMR (Mismatch Repair), HR (Homologous Recombination), and NHEJ (Nonhomologous End Joining). PARP1/2 and BRCA1/2 are relevant in BER and HR pathways, respectively.

DNA repair pathways can be divided into those that respond to SSB and those that respond to DSB. SSB repair pathways include base excision repair (BER), mismatch repair (MMR), and nucleotide excision repair (NER). DSB repair pathways include nonhomologous end joining (NHEJ) and homologous recombination (HR). The proteins involved in these DNA repair pathways are shown in Fig. 1. 

Excision repair. The E. coli mismatch repair is a type of excision repair. However, a different nucleotide excision repair system (NER) is utilized by all organisms from bacteria to human to remove a variety of defects. These include thymine dimers, photohydrates, oxidized bases, adducts of cisplatin (Box 5-B), mutagens derived from polycyclic aromatic compounds,683 and poorly recognized OC mismatched pairs.692 In E. coli this excision repair process depends upon proteins encoded by genes UvrA, B, C, and D and also DNA polymerase I and DNA ligase.693 695a A dimer of protein UvrA forms a complex with helicase UvrB (Eq. 27-22).696 696a... 

Both NER and BER forms of excision repair remove a great variety of defects, many of which are a result of oxidative damage.657 720 Most prominent among these is 7,8-dihydro-8-oxoguanine (8-OG), which is able to base pair with either cytosine (with normal Watson-Crick hydrogen bonding) or with adenine, which will yield a purine-purine mismatch and aC G —> A T transversion mutation (Eq. 27-24), a frequent mutation in human cancers.721 722... 

It is interesting that the original excision repair model is showing a Lazarus effect in explaining mismatch repair and a second excision pathway in the fission yeast, Schizosaccharomyces pombe. 

D. Mu et al., Recognition and repair of compound DNA lesions (base damage and mismatch) by human mismatch repair and excision repair systems. Mol. Cell. Biol. 17,760-769 (1997)... 

DNA Repair. A connection between p53 and DNA repair was observed in p53-deficient cells that exhibited less global DNA repair [197-199] (but see [200]), as well as a reduced capacity to reactivate cisplatin- and UV-damaged reporter plasmids [173][201 ][202]. Furthermore, pretreatment with low levels of UV activated a protective response in which the levels of repair activity were elevated, an effect not observed in p53-deficient cells [202] [203]. It is possible that the p53 protein is directly involved in removing DNA damage since the protein recognizes both irradiated DNA and mismatches [ 162]. There is also evidence that p53 can interact with several components of the excinuclease, including RPA and the TFIIH-associated factors XPB and XPD [204] [205]. So far, however, there is no evidence to demonstrate a direct role for p53 in the nucleotide excision repair pathway. 

Figure 23.13. Bidirectional mismatch repair in mammals studied in vitro. Mismatch repair in vitro can be directed by a strand break located either 5 or 3 to the mismatch. It is likely that in vivo the strand break is provided by the termini of DNA strands that are being synthesized. MutSa, MutSp, and MutLa are involved in mismatch recognition and processing. Exonucleases and other activities are involved in excision. Repair synthesis is carried out by DNA polymerase 8 or e. (Reproduced with permission from Iyer, R. R., Pluciennik, A., Burdett, V., and Modrich, P. L. DNA mismatch repair Functions and mechanism. Chem. Rev.106,302-323, 2006.)...

The importance of the repair of damaged DNA in keeping the cells alive and preventing cancer is also apparent from mutations in genes involved in nucleotide excision repair. The enzymes involved in nucleotide excision repair are other tools that cells have to repair mismatched DNA. Defects in DNA nucleotide excision repair can cause skin cancer (xeroderma pigmentosa) and colon cancer. 

DNA repair is the elimination of covalent DNA modifications and the correction of base mismatches. There are six basic repair categories direct repair, base excision repair, nucleotide excision repair, recombination, cross-link repair, and mismatch repair. 

Schmuiie, C, Vang, A, S-, Beart, R. W., and Jones, R A. (1995). Base CKcision repair of U G mismatches at a mutational hotspot in the p53 gene is more efficient than base excision repair of T G mismatches in extracts of human colon tumors. Cancer Rei. 55,3742-3746. 

Nucleotide-excision repair involves PCNA, DNA polymerase epsilon, and several accessory proteins, such as RF-C (replication factor C), RP-A (replication protein A), and Lig I (DNA ligase I). It could be that these proteins form an aggregate DNA repair machine. PCNA is a hollow circular protein that encircles DNA. PCNA binds and activates many proteins involved in DNA repair. Mismatch repair is less well characterized, but involves DNA polymerase delta. 

With some variability, these general principles apply in nucleotide excision repair (segments of about 30 nucleotides), base excision repair of single bases, and mismatch repair of copying errors (one to five bases). 

D. BRCAl plays a significant role in the repair of double-strand breaks, therefore, since homologous recombination reqnires a cleavage of both strands of a DNA molecule, this event is most likely to be affected by a deficiency in this protein. Thymine dimers, mismatches, and adducts of DNA with carcinogens are effectively removed by a process of excision repair, in which a section of one strand of DNA is removed. 

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