All four known cyclic adducts formed in DNA by the vinyl chloride metabolite chloroacetaldehyde are released by a human DNA glycosylase.
We have previously reported that human cells and tissues contain a 1,N6-ethenoadenine (epsilon A) binding protein, which, through glycosylase activity, releases both 3-methyladenine (m3A) and epsilon A from DNA treated with methylating agents or the vinyl chloride metabolite chloroacetaldehyde, respectively. We now find that both the partially purified human epsilon A-binding protein and cell-free extracts containing the cloned human m3A-DNA glycosylase release all four cyclic etheno adducts--namely epsilon A, 3,N4-ethenocytosine (epsilon C), N2,3-ethenoguanine (N2,3-epsilon G), and 1,N2-ethenoguanine (1,N2-epsilon G). Base release was both time and protein concentration dependent. Both epsilon A and epsilon C were excised at similar rates, while 1,N2-epsilon G and N2,3-epsilon G were released much more slowly under identical conditions. The cleavage of glycosyl bonds of several heterocyclic adducts as well as those of simple methylated adducts by the same human glycosylase appears unusual in enzymology. This raises the question of how such a multiple, divergent activity evolved in humans and what may be its primary substrate.
Dosanjh
M K
MK
Life Sciences Division, Lawrence Berkeley Laboratory, University of California, Berkeley 94720.
Chenna
A
A
Kim
E
E
Fraenkel-Conrat
H
H
Samson
L
L
Singer
B
B
D000079:Acetaldehyde / Q000031:analogs & derivatives* / Q000633:toxicity; D000225:Adenine / Q000031:analogs & derivatives / Q000378:metabolism; D000818:Animals; D001483:Base Sequence; D002417:Cattle; D003596:Cytosine / Q000031:analogs & derivatives / Q000378:metabolism; D004247:DNA / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D045647:DNA Glycosylases; D004268:DNA-Binding Proteins / Q000378:metabolism; D006147:Guanine / Q000031:analogs & derivatives / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D008969:Molecular Sequence Data; D009699:N-Glycosyl Hydrolases / Q000235:genetics / Q000378:metabolism*; D015345:Oligonucleotide Probes
C018289:3,N(4)-ethenocytosine; D004268:DNA-Binding Proteins; C015196:N(2),3-ethenoguanine; D015345:Oligonucleotide Probes; C004981:1,N(6)-ethenoadenine; D006147:Guanine; D003596:Cytosine; D004247:DNA; C004656:chloroacetaldehyde; D045647:DNA Glycosylases; D009699:N-Glycosyl Hydrolases; D000079:Acetaldehyde; D000225:Adenine