Our results present strong evidence supporting the point that DNA repair protein 8-oxoguanine-DNA glycosylase (OGG-1) interacts with autophagy signaling and thereby regulates inflammatory responses in pulmonary hyperoxia. First, we demonstrate that hyperoxia induces cellular damage and DNA injury, inflammatory responses, and increased OGG-1 to facilitate the recognition of DNA damage and also recruits other DNA repair partners to the damage sites (1, 2). Second, we prove that OGG-1 interacts with the autophagy pathway by demonstrating that OGG-1 directly binds to autophagy-related protein 7 (Atg7) and plays a role in regulating nuclear translocation of NF-κB. Although NF-κB phosphorylation is increased in normal lungs under hyperoxia, it is further enhanced in ogg-1 knockout (KO) mice and remarkably augmented in OGG-1 small interfering RNA-transfected cells. Third, we identify that OGG-1 responds to hyperoxic DNA damage and inflammation and that Atg7 deficiency may be attributed to intensified inflammatory responses. Our data show that the interaction between OGG-1 and autophagy regulates inflammatory responses both in vitro and in vivo. Taken together, these findings indicate that the OGG-1/Atg7 axis participates in the regulation of proinflammatory cytokine production through the activation of NF-κB, demonstrating that DNA repair regulates inflammatory responses by coordinating molecular interaction with the key autophagic protein Atg7 in hyperoxic lung injury.

OGG-1, as the initiation protein in the base excision repair pathway, plays an indispensable role in various physiological and pathological processes (1, 2). Besides our recent report (3), OGG-1 may broadly impact many cellular processes in normal and disease states, such as chemotherapy toxicity, airway remodeling, bacterial infection, and neural degeneration (49). Because we have detected DNA damage and OGG-1 function in murine lung epithelial cell line cells, A549 cells, and ogg-1 KO mice in previous reports (39), it may be unnecessary to identify DNA strand breaks in ogg-1 KO mice under hyperoxia although it will be helpful to observe the genetic intervening effects on DNA damage. Our results prove that the inflammation in ogg-1 KO mice is directly related to loss of DNA repair potential, namely, the OGG-1 protein function. Certainly, other mechanisms may also regulate hyperoxic proinflammatory response, and that may require further studies.

Abbreviations used in this article:

Atg7

autophagy-related protein 7

KO

knockout

OGG-1

8-oxoguanine-DNA glycosylase

.

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