The structure of nuclear chromatin may limit the accessibility of carcinogenic agents to DNA. In the case of oxidative DNA strand cleavage mediated by the physiologically relevant iron chelate, iron-ADP, histone-associated nucleosomal DNA is protected while internucleosomal DNA is susceptible to damage. We now find that the distribution of iron-ADP-generated 8-hydroxydeoxyguanosine, a potentially mutagenic oxidative base change, shows relative targeting to internucleosomal sites (3.5-fold increased oxidative modification of internucleosomal compared with nucleosomal DNA as the minimal degree of enrichment). In contrast, iron-EDTA, which generates hydroxyl radical in the 'fluid phase', does not target internucleosomal DNA. Thus, physiologic iron chelates may promote site-specific damage and thereby be relevant to mechanisms of iron-dependent oxidative mutagenesis and carcinogenesis.
Bibliographical noteFunding Information:
We thank L Maidt for technical advice and C.Taubert for preparing the manuscript. Supported in part by National Institutes of Health grants HL30160 and HL37528 (R.P.H.), CA42854 (R A.F.) and IR29CA65021 (H.E.), a University of Minnesota Grant-in-Aid (H.E.) and the Minnesota Medical Foundation.