GC-rich regions in genomes as targets for DNA alkylation.
For many DNA-damaging agents, the extent of damage at any given base site is influenced by the DNA sequence surrounding that site. Most agents that alkylate the guanine N7 position, including mechlorethamine (nitrogen mustard) and benzo[a]pyrene diol epoxide, alkylate oligo-guanine sequences preferentially. Since these data suggest that guanine-cytosine(GC)-rich regions in genes could be preferred sites of damage by these agents, GenBank was searched for genes containing 30 bp sequences of greater than 90% GC (GC runs). While primate, rodent, other mammalian, vertebrate and animal virus genes constituted 57% of the annotated entries, they included 90% of the entries with the GC runs. In addition, the percentage of oncogenes in the group of the entries with GC runs was higher than that in the overall database. One gene of interest containing GC runs was the human c-Ha-ras oncogene. All seven GC runs in the c-Ha-ras gene are in the 5'-flanking region, rather than in the coding sequences. In fact, some of the GC runs are contained in Sp1-binding enhancer sequences. Gel analysis of the alkylation of cloned c-Ha-ras DNA by several carcinogenic alkylating agents strongly suggest that in this gene GC runs can be preferred sites of damage. These observations suggest mechanisms by which DNA damage at sites other than oncogene coding sequences may play a role in carcinogenesis and/or chemotherapy.
Mattes
W B
WB
Environmental Health Center, ICI Americas, Inc., Farmington, CT 06032.
Hartley
J A
JA
Kohn
K W
KW
Matheson
D W
DW
D000477:Alkylating Agents; D000478:Alkylation; D000818:Animals; D001483:Base Sequence; D004247:DNA; D004249:DNA Damage; D004279:DNA, Viral; D004742:Enhancer Elements, Genetic; D006133:Growth Substances; D006801:Humans; D008969:Molecular Sequence Data; D009857:Oncogenes; D012045:Regulatory Sequences, Nucleic Acid; D013539:Simian virus 40 / Q000235:genetics; D013329:Structure-Activity Relationship
D000477:Alkylating Agents; D004279:DNA, Viral; D006133:Growth Substances; D004247:DNA