Repair proteins mismatched

Obmolova, G., Ban, C., Hsieh, P. and Yang, W. (2000). Crystal structures of mismatch repair protein MutS and its complex with a substrate DNA. Nature 407, 703-710. 

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. 

Mismatch repair protein mutL Single-stranded DNA-binding protein ssb DNA repair uvrA Helicase dnaB RNA polymerase frpoB subunits rpoCJ... 

Francia G, Green SK, Bocci G, et al. Down-regulation of DNA mismatch repair proteins in human and murine tumor spheroids implications for multicellular resistance to alkylating agents. Mol Cancer Ther. 2005 4 1484-1494. 

A more direct association was made by experiments showing that cis-platin-modified DNA is recognized by mismatch repair proteins. The Mut-S a heterodimer, a putative mismatch recognition factor, binds to a 32-bp... 

Fig. 4. Possible role of mismatch repair in the cytotoxicity of cisplatin. A) During replicative bypass, a mismatch is incorporated across from the cisplatin-DNA adduct. This compound lesion is bound by the mismatch repair proteins, which cut the DNA on the strand opposite the platinum. Repair synthesis would reproduce the same mismatch, resulting in a futile cycle and possibly the accumulation of DNA strand breaks which would activate apoptosis. B) Alternatively, the mismatch repair complex can recognize the cisplatin-DNA adduct alone and generate a signal that triggers apoptosis.

Cellular sensitivity to different platinum compounds and the recognition of the platinum DNA adducts by mismatch repair protein complexes appear to be linked [103]. It may also be significant that hMSH2 is expressed to higher levels in testicular and ovarian tissue than in other organs such as heart, liver and colon [109], Whether or not mismatch repair plays a general role in the anticancer activity of cisplatin still remains debatable, however. Mismatch repair proteins bind to cisplatin-DNA adducts in vitro with weak specificity [109][113]. Although specificity is enhanced when aplat-inum lesion is combined with a mutation [113], it is still less than the affinity of these proteins for the unplatinated mutation [63] [108]. 

McGoldrick JP, Yeh YC, Solomon M, Essigmann JM, Lu AL (1995) Characterization of a mammalian homolog of the Escherichia-coli Muty mismatch repair protein. Mol Cell Biol 15 989-996... 

Culligan KM, Meyer-Gauen G, Lyons-Weiler J, Hays JB (2000) Evolutionary origin, diversification and specialization of eukaryotic MutS homolog mismatch repair proteins. Nucleic Acids Res 28 463-471... 

B.B., Crit. Rev. Immunol. 24, 297-320, 2004 Fiset, P.O., Cameron, L., and Hamid, Q., Local isotype switching to IgE in airway mucosa, J. Allergy Clin. Immunol. 116, 233-236, 2005 Min, I.M. and Seising, E., Antibody class switch recombination roles for switch seqences and mismatch repair proteins, Adv. Immunol. 87, 297-328, 2005 Apian, P.D., Causes of oncogenic chromosomal translocation. Trends Genet. 22, 46-55, 2006. 

Metallointercalators that selectively and efficiently target single base mismatches have found several applications both as biologic probes and as potential chemotherapeutic agents. For instance, [Rh(bpy)2phzi] + was used to probe the relative frequency of mismatched sites in cell lines deficient versus proficient in their mismatch repair machinery (18). The relative cleavage observed with the phzi complex in healthy cell lines was low compared with that in cancer cell lines that carried mutations in essential repair proteins. These results support previous studies on the association of mismatch repair deficiency and cancer. 

Figure 27.51. Mismatch Repair. DNA mismatch repair in E. coli is initiated by the interplay of MutS, MutL, and MutH proteins. A G-T mismatch is recognized by MutS. MutH cleaves the backbone in the vicinity of the mismatch. A segment of the DNA strand containing the erroneous T is removed by exonuclease I and synthesized anew by DNA polymerase III. [After R. F. Service. Science 263(1994) 1559.]...

Stains for the mismatch repair proteins MLH1, MSH2, MSH6, and PMS2 can be used to screen for MSI-high neoplasms. 

A subset of colorectal cancers arises via the MSI pathway owing to mutations or alterations in specific mismatch repair proteins. This pathway is discussed further later. 

MSI-H/mismatch repair protein-deficient colorectal cancers, evaluated by either MSI testing or IHC, may have a better survival in subsets of colon cancer patients. This effect may be related to the CpG island methylator phenotype (widespread promoter methyla-tion). MSI-H tumors may also respond differently to... 

Medullary carcinomas of the pancreas, like their colorectal counterparts, often show microsatellite instability, which is usually caused by somatic hypermethyl-ation of the MLHl promoter in sporadic cases " and by an inherited mutation in MLHl or MSH2 HNPCC syndrome.Immunolabeling for MLHl and MSH2 reveals loss of expression of one of these DNA mismatch repair proteins in many cases. 

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