Purine Stretches Are Avoided by Cancer Mutations ^†

Purine stretches, sequences of adenine (A) and guanine (G) in DNA, play critical roles in binding regulatory protein factors and influence gene expression by affecting DNA folding. Both purines can exist in the enol-amine form (often referred to as the imidazole form) and keto-imine forms. The enol-amine form is more stable and biologically significant than the keto-imine form. This enhanced stability is attributed to the fully conjugated ring system in the enol-amine form, which adheres to Hückel’s rule and becomes aromatic. The presence of a delocalized pi-electron cloud within this fully conjugated ring system results in an aromatic molecule. In contrast, the keto-imine form lacks full conjugation in its ring system due to a broken double bond between the nitrogen and carbon atoms, rendering it non-aromatic. This study investigates the relationship between purine stretches and cancer development, which makes mechanistic sense considering the aromaticity of purines in the purine stretches flanking each mutation. A pronounced avoidance of typical cancer mutations of long purine stretches in typical types of cancer was observed in the public data of patients in intergenic regions, suggesting the role of intergenic sequences in chromatin reorganization and gene regulation. A statistically significant shortening of purine stretches in cancerous tumors (p-value 0.0001) was found. The insights into the aromatic nature of purines and their stacking energies explain the role of purine stretches in DNA structure, contributing to their role in cancer progression. This research lays the groundwork for understanding the nature of purine stretches, emphasizing their importance in gene regulation and chromatin restructuring, and offers potential avenues for novel cancer therapies and insights into cancer etiology.