Oxidative lesions modulate G-quadruplex stability and structure in the human BCL2 promoter

Abstract

Abstract Misregulation of BCL2 expression has been observed with many diseases and is associated with cellular exposure to reactive oxygen species. A region upstream of the P1 promoter in the human BCL2 gene plays a major role in regulating transcription. This G/C-rich region is highly polymorphic and capable of forming G-quadruplex structures. Herein we report that an oxidative event simulated with an 8-oxo-7,8-dihydroguanine (oxoG) substitution within a long G-tract results in a reduction of structural polymorphism. Surprisingly, oxoG within a 25-nt construct boosts thermal stability of the resulting G-quadruplex. This is achieved by distinct hydrogen bonding properties of oxoG, which facilitate formation of an antiparallel basket-type G-quadruplex with a three G-quartet core and a G·oxoG·C base triad. While oxoG has previously been considered detrimental for G-quadruplex formation, its stabilizing effect within a promoter described in this study suggests a potential novel regulatory role of oxidative stress in general and specifically in BCL2 gene transcription.