Reactive oxygen species (ROS) is essential for NETosis. Nevertheless, how ROS induce NETosis at baseline and during neutrophil activation are unknown. Although neutrophils carry DNA transcription, replication and repair machineries, their relevance in the short-lived mature neutrophils that carry pre-synthesized proteins has remained a mystery for decades. Our recent studies show that (i) NETosis-inducing agonists promote NETosis-specific kinase activation, genome-wide transcription that helps to decondense chromatin, and (ii) excess ROS produced by NADPH oxidase activating agonists generate genome-wide 8-oxy-guanine (8-OG), and the initial steps of DNA repair are needed to decondense chromatin in these cells. These steps require DNA repair proteins necessary for the assembly and nicking at the damaged DNA sites (PARP, APE1 and Ligase), but not the enzymes that mediate the repair DNA synthesis (DNA polymerase and PCNA). In this study, we show that inhibition of DNA damage repair proteins PCNA and DNA polymerase drastically promotes baseline NETosis. Hence, these findings suggest that in the absence of active transcription, DNA repair mediated by PCNA and DNA polymerase is essential to prevent chromatin decondensation and spontaneous NETosis. These findings indicate that ROS, oxidative DNA damage, transcription and DNA repair differentially regulate spontaneous and agonist-induced NETosis. Therefore, context matters.