SEQUENCE DETERMINANTS FOR -2-FRAMESHIFT MUTAGENESIS AT NARI-DERIVED HOT-SPOTS

被引:38
作者
KOFFELSCHWARTZ, N
FUCHS, RPP
机构
关键词
N-2-ACETYLAMINOFLUORENE; FRAMESHIFT MUTAGENESIS; MUTATION HOT SPOTS; FLANKING NUCLEOTIDE EFFECTS; SLIPPAGE MUTAGENESIS;
D O I
10.1006/jmbi.1995.0515
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The recognition sequence of the NarI restriction enzyme is known to be a strong hot spot for -2 frameshift mutations (G(1)G(2)CG(3)CC-->GGCC) induced by the chemical carcinogen N-2-acetylaminofluorene (AAF). In an attempt to define a ''consensus sequence'' for this mutation hot spot, we have investigated the role of the bases flanking the central dinucleotide GpC repeat in the NarI sequence (N(a)GCGCN(b)) on the mutation frequency induced by the carcinogen. Construction and random modification with AAF of the 16 plasmids resulting from the replacement of N-a and N-b by A,T,G and C, respectively, have been undertaken. All 16 sequences tested are found to be -2 frameshift mutation hot spots. Indeed, a level of modification of approximately five AAF adducts per plasmid molecule induces a mutation frequency ranging between 500 and 5000-fold above background. The mutations observed are mainly (90 %) deletion of a dinucleotide CpG in the targeted sequence N(a)GCGCN(b). Previous studies on NarI mutagenesis (G(1)G(2)CG(3)CC-->GGCC) have shown that only AAF adducts at G(3)in the template for lagging strand synthesis induce -2 frameshift mutagenesis at a high level. When the mutation data obtained in this work are analyzed as originating essentially from adducts to guanines in this strand, we find that it is the nucleotide N-b located 3' to the central dinucleotide GpC repeat that strongly modulates the mutation frequency, while the nucleotide N-a located on the 5' side has little effect. Our present model of frameshift mutagenesis at NarI sites involves a template-primer misalignment step with a two-nucleotide slipped mutagenic intermediate. In the context of this model, the modulation of mutagenesis by nucleotide N-b located two nucleotides 3' from the putative adduct site in the template strand can be explained in view of the fact that the replication complex encounters this nucleotide before it encounters the adduct. (C) 1995 Academic Press Limited
引用
收藏
页码:507 / 513
页数:7
相关论文
共 17 条
[1]   INFLUENCE OF RECA PROTEIN ON INDUCED MUTAGENESIS [J].
BLANCO, M ;
HERRERA, G ;
COLLADO, P ;
REBOLLO, JE ;
BOTELLA, LM .
BIOCHIMIE, 1982, 64 (8-9) :633-636
[2]   SINGLE ADDUCT MUTAGENESIS - STRONG EFFECT OF THE POSITION OF A SINGLE ACETYLAMINOFLUORENE ADDUCT WITHIN A MUTATION HOT SPOT [J].
BURNOUF, D ;
KOEHL, P ;
FUCHS, RPP .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1989, 86 (11) :4147-4151
[3]   HOT SPOTS OF FRAMESHIFT MUTATIONS INDUCED BY THE ULTIMATE CARCINOGEN N-ACETOXY-N-2-ACETYLAMINOFLUORENE [J].
FUCHS, RPP ;
SCHWARTZ, N ;
DAUNE, MP .
NATURE, 1981, 294 (5842) :657-659
[4]  
GARCIA A, 1993, P NATL ACAD SCI USA, V90, P5989, DOI 10.1073/pnas.90.13.5989
[5]   ISOLATION AND CHARACTERIZATION OF MUTANTS OF ESCHERICHIA-COLI DEFICIENT IN INDUCTION OF MUTATIONS BY ULTRAVIOLET-LIGHT [J].
KATO, T ;
SHINOURA, Y .
MOLECULAR & GENERAL GENETICS, 1977, 156 (02) :121-131
[6]   GENETIC-CONTROL OF AAF-INDUCED MUTAGENESIS AT ALTERNATING GC SEQUENCES - AN ADDITIONAL ROLE FOR RECA [J].
KOFFELSCHWARTZ, N ;
FUCHS, RPP .
MOLECULAR & GENERAL GENETICS, 1989, 215 (02) :306-311
[7]   CARCINOGEN-INDUCED MUTATION SPECTRUM IN WILD-TYPE, UVRA AND UMUC STRAINS OF ESCHERICHIA-COLI - STRAIN SPECIFICITY AND MUTATION-PRONE SEQUENCES [J].
KOFFELSCHWARTZ, N ;
VERDIER, JM ;
FREUND, MBAM ;
DAUNE, MP ;
FUCHS, RPP .
JOURNAL OF MOLECULAR BIOLOGY, 1984, 177 (01) :33-51
[8]   CARCINOGEN-INDUCED FRAMESHIFT MUTAGENESIS IN REPETITIVE SEQUENCES [J].
LAMBERT, IB ;
NAPOLITANO, RL ;
FUCHS, RPP .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1992, 89 (04) :1310-1314
[9]   A UMUDC-INDEPENDENT SOS PATHWAY FOR FRAMESHIFT MUTAGENESIS [J].
MAENHAUTMICHEL, G ;
JANELBINTZ, R ;
FUCHS, RPP .
MOLECULAR & GENERAL GENETICS, 1992, 235 (2-3) :373-380
[10]  
MIHLE C, 1994, NUCLEIC ACIDS RES, V22, P4646