Repair, mismatch

One striking question relates to how defects in the same gene—for example, XPD—produce three different disease states XP, XP-CS, and TTD. Mutations that cause the different diseases, in general, reside in different regions of the XPD gene. A more in-depth answer is complex and outside the scope of this chapter. Readers are referred to the Friedberg et al. book listed at the end of this chapter for a more detailed discussion of this fascinating question. 

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In vitro nifedipine inhibits proliferation of colon cancer cells with a DNA mismatch repair defect that are resistant to 5-fluorouracil. Whether this also... 

Mismatch repair Copying errors (single base or two- to five-base unpaired loops) Methyl-directed strand cutting, exonuclease digestion, and replacement... 

Faulty mismatch repair has been finked to fieredi-tary nonpolyposis colon cancer (HNPCC), one of die most common inherited cancers. Genetic smdies finked HNPCC in some families to a region of cfiromosome 2. The gene located, designated hMSH2, was sub-sequendy shown to encode the human analog of the... 

Figure 36-22. Mismatch repair of DNA. This mechanism corrects a single mismatch base pair (eg, C to A rather than T to A) or a short region of unpaired DNA. The defective region is recognized by an endonuclease that makes a single-strand cut at an adjacent methylated GATC sequence. The DNA strand is removed through the mutation, replaced, and religated.

MSH2, MLH1, PM SI, DNA mismatch repair enzymes Hereditary nonpolyposis colorectal cancer... 

DNA mismatch repair genes Genes that identify and correct errors in DNA base pairs during DNA replication. Mutations in the mismatch repair genes can lead to cancer by allowing abnormal cells to continue to grow. 

Heteroduplex recombination involves preparing single-stranded DNA from two different homologous genes and mixing them to form heteroduplexes. These heteroduplexes are then transformed into a host that then creates hybrid homoduplexes through in vivo mismatch repair mechanisms [22]. 

Without regard to therapy, potentially valuable diagnostic tests are available for presymptomatic evaluation of risk of breast cancer due to predisposition from BRCA 1 or BRCA 2 and of colon cancer related to familial adenomatous polyposis (APC gene) or hereditary nonpolyposis mismatch repair genes (MSH 2). Genetic predisposition to Alzheimer disease associated with ApoE4 is neither sufficient nor necessary to lead to the clinical condition, and no definitive therapy is available. 

Mismatch Repair. Mispairs that break the normal base-pairing rules can arise spontaneously due to DNA biosynthetic errors, events associated with genetic recombination and the deamination of methylated cytosine (Modrich, 1987). With the latter, when cytosine deaminates to uracil, an endonuclease enzyme, /V-uracil-DNA glycosylase (Lindahl, 1979), excises the uracil residue before it can pair with adenine at the next replication. However, 5-methyl cytosine deaminates to form thymine and will not be excised by a glycosylase. As a result, thymine exits on one strand paired with guanine on the sister strand, that is, a mismatch. This will result in a spontaneous point mutation if left unrepaired. For this reason, methylated cytosines form spontaneous mutation hot-spots (Miller, 1985). The cell is able to repair mismatches by being able to distinguish between the DNA strand that exists before replication and a newly synthesized strand. 

A second group of inherited colon cancers are termed hereditary nonpolyposis colorectal cancer (HNPCC). HNPCC may account for 5% of all colon cancer cases and can be caused by mutations in any of five different genes. All of these genes encode proteins involved in DNA mismatch repair (Fig II-5-3). As with inherited breast cancer, fiiulty DNA repair leads to mutated cells capable of producing tumors. 

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. ... 

Aebi S, Kurdi-Haidar B, Gordon R, Cenni B, Zheng H, Fink D, Christen RD, Boland RC, Koi N, Fishel R, Howell SB (1996) Loss of DNA mismatch repair. in acquired resistance to cisplatin. Cancer Res 56 3087-3090... 

Dean N, McKay R, Miraglia L, Howard R, Cooper S, Giddings ], Nicklin P, Meister L, Ziel R, Geiger T, Muller M, Fabbro D (19 ) Iidiibition of growth of human tumor cell lines in nude mice by an antisense oligonucleotide inhibitor of protein kinase C-a expression. Cancer Res 56 3499-3507 Defranco AL (1991) Immunosuppressants at work. Nature 352 754-755 De las Alas MM, Aebi S, Fink D, Howell SB, Los G (1997) Loss of DNA mismatch repair effects on the rate of mutation to drug resistance. J Natl Cancer Inst 89 1537-1541... 

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. 

Martin SA, Hewish M, Sims D et al (2011) Parallel high-throughput RNA interference screens identify PINKl as a potential therapeutic target for the treatment of DNA mismatch repair-deficient cancers. Cancer Res 71 1836-1848... 

Rodriguez-Jimenez FJ, Moreno-Manzano V, Lucas-Dominguez R et al (2008) Hypoxia causes downregulation of mismatch repair system and genomic instabUity in stem cells. Stem CeUs 26 2052-2062... 

Modrich P. Strand-specific mismatch repair in mammalian cells. J Biol Chem 1997 272 24,727-24,730. 

Durant ST, Morris MM, Bland M, et al. Dependence on RAD52 and RADI for anticancer drug resistance mediated by inactivation of mismatch repair genes. Current Biology 1999 9 51-54. 

Friedman HS, McLendon RE, Kerby T, et al. DNA mismatch repair and 06-alkylguanine-DNA alkyltransferase analysis and response to Temodal in newly diagnosed malignant glioma. J Clin Oncol 1998 16 3851-3857. 

Mismatch repair involves elements of both base-excision and nucleotide excision mechanisms. 

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