EFFECT OF IONIC-STRENGTH AND CATIONIC DNA AFFINITY BINDERS ON THE DNA-SEQUENCE SELECTIVE ALKYLATION OF GUANINE N7-POSITIONS BY NITROGEN MUSTARDS

被引:31
作者
HARTLEY, JA
FORROW, SM
SOUHAMI, RL
机构
[1] Department of Oncology, University College, Middlesex School of Medicine, London WIP 8BT
关键词
D O I
10.1021/bi00464a014
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
Large variations in alkylation intensities exist among guanines in a DNA sequence following treatment with chemotherapeutic alkylating agents such as nitrogen mustards, and the substituent attached to the reactive group can impose a distinct sequence preference for reaction. In order to understand further the structural and electrostatic factors which determine the sequence selectivity of alkylation reactions, the effect of increased ionic strength, the intercalator ethidium bromide, AT-specific minor groove binders distamycin A and netropsin, and the polyamine spermine on guanine N7-alkylation by l-phenylalanine mustard (l-Pam), uracil mustard (UM), and quinacrine mustard (QM) was investigated with a modification of the guanine-specific chemical cleavage technique for DNA sequencing. For l-Pam and UM, increased ionic strength and the cationic DNA affinity binders dose dependently inhibited the alkylation. QM alkylation was less inhibited by salt (100 mM NaCl), ethidium (10 μM), and spermine (10;μM). Distamycin A and netropsin (100 μM) gave an enhancement of overall QM alkylation. More interestingly, the pattern of guanine N7-alkylation was qualitatively altered by ethidium bromide, distamycin A, and netropsin. The result differed with both the nitrogen mustard (l-Pam < UM < QM) and the cationic agent used. The effect, which resulted in both enhancement and suppression of alkylation sites, was most striking in the case of netropsin and distamycin A, which differed from each other. DNA footprinting indicated that selective binding to AT sequences in the minor groove of DNA can have long-range effects on the alkylation pattern of DNA in the major groove. © 1990, American Chemical Society. All rights reserved.
引用
收藏
页码:2985 / 2991
页数:7
相关论文
共 42 条
[1]  
BOLES TC, 1984, P NATL ACAD SCI USA, V74, P560
[2]   DISTAMYCINS INHIBIT THE BINDING OF OTF-1 AND NFE-1 TRANSFACTORS TO THEIR CONSERVED DNA ELEMENTS [J].
BROGGINI, M ;
PONTI, M ;
OTTOLENGHI, S ;
DINCALCI, M ;
MONGELLI, N ;
MANTOVANI, R .
NUCLEIC ACIDS RESEARCH, 1989, 17 (03) :1051-1059
[3]   SPECIFIC ACTIVATION OF TRANSCRIPTION INITIATION BY THE SEQUENCE-SPECIFIC DNA-BINDING AGENTS DISTAMYCIN-A AND NETROPSIN [J].
BRUZIK, JP ;
AUBLE, DT ;
DEHASETH, PL .
BIOCHEMISTRY, 1987, 26 (03) :950-956
[4]  
CHUN EHL, 1969, CANCER RES, V29, P1184
[5]  
EWIG RAG, 1977, CANCER RES, V37, P2114
[6]  
FESSEN MR, 1988, P AM ASSOC CANC RES, V29, pA1095
[7]   FOOTPRINTING AT LOW-TEMPERATURES - EVIDENCE THAT ETHIDIUM AND OTHER SIMPLE INTERCALATORS CAN DISCRIMINATE BETWEEN DIFFERENT NUCLEOTIDE-SEQUENCES [J].
FOX, KR ;
WARING, MJ .
NUCLEIC ACIDS RESEARCH, 1987, 15 (02) :491-507
[8]  
FOX KR, 1984, NUCLEIC ACIDS RES, V12, P211
[9]  
Gale EF, 1981, MOL BASIS ANTIBIOTIC
[10]   THE BIOLOGICAL ACTIONS AND THERAPEUTIC APPLICATIONS OF THE B-CHLOROETHYL AMINES AND SULFIDES [J].
GILMAN, A ;
PHILIPS, FS .
SCIENCE, 1946, 103 (2675) :409-&