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Divergent effects of oxidatively induced modification to the C8 of 2′‐deoxyadenosine on transcription factor binding: 8,5′(S)‐cyclo‐2′‐deoxyadenosine inhibits the binding of multiple sequence specific transcription factors, while 8‐oxo‐2′‐deoxyadenosine increases binding of CREB and NF‐kappa B to DN

DNA is exposed to endogenous and environmental factors that can form stable lesions. If not repaired, these lesions can lead to transcription/replication blocking or mutagenic bypass. Our previous work has focused on 8,5′‐cyclopurine 2′‐deoxyribonucleosides, a unique class of oxidatively induced DNA lesions that are specifically repaired by the NER pathway (see Brooks PJ [ 2008 ]: DNA Repair 7:1168–1179). Here we used EMSA to monitor the ability of sequence‐specific transcription factors, HSF1, CREB, and NF‐kappaB and “architectural” transcription factor, HMGA, to bind to their target sequences when 8, 5′(S)‐cyclo‐2′‐deoxyadenosine (cyclo‐dAdo) is present within their recognition sequences. For comparison, we also tested the effect of 8‐oxo‐7,8‐dihydro‐2′‐deoxyadenosine (8‐oxo‐dAdo) in the same recognition sequences. The presence of a cyclo‐dAdo lesion in the target sequence essentially eliminated the binding activity of HSF1, CREB, and NF‐kappa B whereas HMGA retained some of its binding activity. In contrast, 8‐oxo‐dAdo had no obvious effect on the binding activity of HSF1 and HMGA in comparison to lesion‐free DNA. Notably, though, CREB and NFκB binding increased when an 8‐oxo‐dAdo lesion was present in their target sequence. Competition EMSA showed about 2–3‐fold increased affinity of both proteins for the 8‐oxo‐dAdo containing target sequence compared to lesion‐free DNA. Molecular modeling of the lesions in the NF‐kappaB sequence indicated that 8‐oxo‐dAdo may form an additional hydrogen bond with the protein, thereby strengthening the binding of NF‐kappa B to its DNA target. The cyclo‐dAdo lesion, in contrast, distorted the DNA structure, providing an explanation for the inhibition of NF‐kappaB binding. Environ. Mol. Mutagen., 2011. © 2010 Wiley‐Liss, Inc.