Mutation hot spots

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. 

Steighner RJ, Povirk LF (1990) Bleomycin-induced DNA lesions at mutational hot spots imphcations for the mechanism of double-strand cleavage. Proc Natl Acad Sci USA 87(21) 8350-8354 Straney DC, Crothers DM (1987) Effect of drug-DNA interactions upon transcription initiation at the lac promoter. Biochemistry 26(7) 1987-1995... 

Allen, J. D., Jackson, S. C., and Schinkel, A. H. (2002) A mutation hot spot in the BCRPl (ABCG2) multidrug transporter in mouse cell fines selected for doxorubicin resistance. Cancer Res. 62, 2294-2299. 

Levin, D.E., Yamasaki, E. Ames, B.N. (1982) A new Salmonella tester strain, TA97, for the detection of frameshift mutagens. A nm of cytosines as a mutational hot-spot. Mutat. Res., 94, 315-330... 

The helix termination motif may well be unique in containing so many special features of structural and functional importance in such a short length of sequence. Indeed, the experimental observation that the C-terminal end of segment 2B was a mutation hot spot that would lead to a large number of diseases (Parry and Steinert, 1999) was readily predictable on theoretical grounds. There are, as stated above, a multitude of key residues in this region that are involved in almost every aspect of the structure and assembly of IF molecules. 

Schlichtholz, B., Legros, Y., Gillet, D., Gaillard, C., Marty, M., Lane, D., Calvo, F., and Soussi, T. 1992. The immune response to p53 in breast cancer patients is directed against immunodominant epitopes unrelated to the mutational hot spot. Cancer Res. 52 6380-6384. 

The problem with a genetic approach to investigating BH4 responsiveness is that (1) there is no evidence that the BH4-binding site represents a mutational hot spot, and (2) mutations outside the known BH4-binding site also have been shown to produce a BH4-responsive PAH (Bernegger and Blau, 2002 Steinfeld et al., 2001). The dissociation between the location of the mutation in the x-ray crystal structure and... 

Benzo[a]pyrene diol epoxides react with adenine residues in DNA to give 105(-l-)- and 10R(-)-tra s-anti-benzo[a]pyrene-N -dA adducts (103), lOR(-) shown, which give rise to mutational hot spots. The solution structure of an 11-mer duplex in which there is a modified adenine has been studied, and it was... 

Magewu, A, and Jones, P. A. (1994). Ubiquitous and tenacious methylation of the CpGsite in codon 248 of the p53 gene may explain its frequent appearance as a mutational hot spot in human cancer. Mol. Ceil. Biot. 14, 4225-4232. 

Most patients are heteroallehc unless their parents are consanguineous. More than 30 separate mutations have been identified C73R is at a mutation hot spot in the gene and has been found on 34% of alleles investigated to date. Geno-... 

The DNA sequence M, shown below, is the sense strand from a coding region known to be a mutational hot spot for a gene. It encodes amino acids 21 to 25. Given the genetic and amino acid codes CCC = proline (P), GCC = alanine (A), TTC = phenylalanine (F), and TAG = stop codon, which of the following sequences is a frame-shift mutation that causes termination of the encoded protein ... 

Bumouf, D., Koehl, P., and Fuchs, R.P.P. (1989) Single adduct mutagenesis strong effect of the position of a single acetylaminofluorene adduct within a mutation hot spot. Proc. Natl Acad. Sci. USA, 86, 4147-4151. 

Fuchs, R.P.P. and Fujii, S. (2007) Translesion synthesis in Escherichia coli lessons from the Narl mutation hot spot. DNA Repair (Amst.), 6,1032-1041. 

Buterin, T., Hess, M.T., Luneva, N., Geadntov, N.E., Amin, S., Kroth, H., Seidel, A., and Naegeli, H. (2000) Unrepaired fjord region polycyclic aromatic hydrocarbon-DNA adduds in ras codon 61 mutational hot spots. 

Hanrahan, C.J., Bacolod, M.D., Vyas, R.R., Liu, T., Geacintov, N.E., Loechler, E.L., and Basu, A.K. (1997) Sequence specific mutagenesis of the major (+)- nti-benzo[a]pyrene diol epoxide-DNA adduct at a mutational hot spot in vitro and in Escherichia coli cells. Chem. Res. Toxicol, 10, 369-377. 

Yan, S., Shapiro, R., Geadntov, N.E., and Broyde, S. (2001) Stereochemical, structural, and thermodynamic origins of stability differences between stereoisomeric benzojajpyrene diol epoxide deoxyadenosine adduds in a DNA mutational hot spot sequence. 

Mutations within the DNA sequences of genes Mutations could be located anywhere within the genes. However, in some genes mutations are clustered around mutational hot spots. 

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