Insertions protein synthesis mutations

HbA) have been reported. These molecules often differ from HbA by the insertion of an incorrect amino acid into either the a- or P-chains during protein synthesis. Other variants may be due to deletion or frameshift mutations (Section 17.7). Haemoglobin variants may function normally or abnormally depending on the nature and position of the substitution (Table 4.5). 

Translesion synthesis with DNA Pol of the A-acetyl-2-aminofluorene adduct of guanosine (88) is inefficient with templates containing (88). In the presence of the Revl protein, translesion synthesis occurs and dCTP is the major nucleotide incorporated opposite it, and studies with a mutant DNA Pol I gave similar results. Benzo[a]pyrene is a potent environmental carcinogen, which when metabolised leads to u t -benzo[a]pyrene-7,8-dihydrodiol-9,10-epoxide anti-BPDE). With dG, the major lesion is (+)-tra w-a h-B[a]P-A -dG, (89), and is usually repaired by the nucleotide excision repair (NER) pathway. The translesion synthesis past (89) has been examined with a number of polymerases. With human RNA Pol II, (89) is a block to synthesis, whilst DNA Pol k preferentially incorporated the correct nucleotide. In yeast cells, Pol induced a large number of mutations involving Pol p, whilst Pol p alone contributed to 1-3 deletions or insertions. The NER of (89) with UvrB proteins was also studied. ... 

The genetic mutations are mainly deletions, but insertions or duphcations also occur, as well as missense and nonsense point mutations (see Fig. 34.20). Four classes of mutations have been identified. The first class involves null alleles that either direct the synthesis of no protein at all or a protein that cannot be precipitated by antibodies to the LDL receptor. In the second class, the alleles encode proteins, but they cannot be transported to the cell surface. The third class of mutant alleles encodes proteins that reach the cell surface but cannot bind LDL normally. Finally, the fourth class encodes proteins that reach the surface and bind LDL but fail to cluster and internalize the LDL particles. The result of each of these mutations is that blood levels of LDL are elevated because cells cannot take up these particles at a normal rate. 

Figure 28.28 on page 800 of the text gives an example of how a base-change mutation within an intron in the (l-globin gene can produce a 3 splice site upstream from the normal 3 splice site. The result is that five amino acids not normally present in the protein are inserted into the chain before synthesis is terminated by a stop codon. 

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