G-quadruplex–forming promoter sequences enable transcriptional activation in response to oxidative stress

Abstract

Oxidative DNA damage is an implacable consequence of aerobic metabolism and often exacerbated in inflammatory processes that use reactive oxygen species (ROS) both as signaling molecules and as chemical warfare against pathogens. An extensive body of work, recently reviewed in ref. 1, has highlighted the deleterious consequences of oxidative DNA damage, which involves oxidized nucleobases that, if left unrepaired, are either mutagenic or strong replication blockers. Most oxidative DNA damage is efficiently processed by DNA repair pathways, primarily base excision repair (BER), the molecular details of which are generally well understood (2). However, an emerging area of research posits that certain oxidative DNA lesions and their associated repair complexes are intermediates in a signaling transduction cascade that uses ROS as secondary messengers to ultimately effect transcriptional regulation (3⇓⇓⇓–7). In PNAS, Fleming et al. (8) reinforce these notions by describing a compelling mechanism by which 8-oxoguanine (OG), a canonical oxidative DNA damage product, when occurring in guanine-rich, G-quadruplex–forming promoter sequences, directly up-regulates transcription of the downstream gene.