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 DNA

• DOI: 10.1002/em.20619
• Publication Date: 2010-09-24T19:12:23Z
• Authors: Jessy Abraham; Philip J. Brooks
• Keywords: Deoxyadenosine; Transcription

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