Enhanced sensitivity of Neil1-/-mice to chronic UVB exposure.
Oxidative stress and reactive oxygen species (ROS)-induced DNA base damage are thought to be central mediators of UV-induced carcinogenesis and skin aging. However, increased steady-state levels of ROS-induced DNA base damage have not been reported after chronic UV exposure. Accumulation of ROS-induced DNA base damage is governed by rates of lesion formation and repair. Repair is generally performed by Base Excision Repair (BER), which is initiated by DNA glycosylases, such as 8-oxoguanine glycosylase and Nei-Endonuclease VIII-Like 1 (NEIL1). In the current study, UV light (UVB) was used to elicit protracted low-level ROS challenge in wild-type (WT) and Neil1-/-mouse skin. Relative to WT controls, Neil1-/-mice showed an increased sensitivity to tissue destruction from the chronic UVB exposure, and corresponding enhanced chronic inflammatory responses as measured by cytokine message levels and profiling, as well as neutrophil infiltration. Additionally, levels of several ROS-induced DNA lesions were measured including 4,6-diamino-5-formamidopyrimidine (FapyGua), 2,6-diamino-4-hydroxy-5-formamidopyrimidine (FapyAde), 8-hydroxyguanine (8-OH-Gua), 5,6-dihydroxyuracil (5,6-diOH-Ura) and thymine glycol (ThyGly). In WT mice, chronic UVB exposure led to increased steady-state levels of FapyGua, FapyAde, and ThyGly with no significant increases in 8-OH-Gua or 5,6-diOH-Ura. Interestingly, the lesions that accumulated were all substrates of NEIL1. Collectively, these data suggest that NEIL1-initiated repair of a subset of ROS-induced DNA base lesions may be insufficient to prevent the initiation of inflammatory pathways during chronic UV exposure in mouse skin.
Oregon Institute of Occupational Health Sciences, Oregon Health & Science University Portland, OR 97239-3098, United States.
Marcus J
MJ
Calkins
Oregon Institute of Occupational Health Sciences, Oregon Health & Science University Portland, OR 97239-3098, United States.
Vladimir
V
Vartanian
Oregon Institute of Occupational Health Sciences, Oregon Health & Science University Portland, OR 97239-3098, United States.
Nichole
N
Owen
Biomolecular Measurement Division, National Institute of Standards and Technology, Gaithersburg MD 20899-8311, United States.
Guldal
G
Kirkali
Biomolecular Measurement Division, National Institute of Standards and Technology, Gaithersburg MD 20899-8311, United States.
Pawel
P
Jaruga
Biomolecular Measurement Division, National Institute of Standards and Technology, Gaithersburg MD 20899-8311, United States.
Miral
M
Dizdaroglu
Oregon Institute of Occupational Health Sciences, Oregon Health & Science University Portland, OR 97239-3098, United States; Department of Molecular and Medical Genetics, Oregon Health & Science University Portland, OR 97239-3098, United States.
Amanda K
AK
McCullough
Oregon Institute of Occupational Health Sciences, Oregon Health & Science University Portland, OR 97239-3098, United States; Department of Physiology and Pharmacology, Oregon Health & Science University Portland, OR 97239-3098, United States. Electronic address: lloydst@ohsu.edu.
R Stephen
RS
Lloyd
D000818:Animals; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D004249:DNA Damage; D045647:DNA Glycosylases / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D004260:DNA Repair; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006147:Guanine / Q000031:analogs & derivatives / Q000378:metabolism; D007249:Inflammation / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D020556:Neutrophil Infiltration / Q000528:radiation effects; D018384:Oxidative Stress; D011743:Pyrimidines / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000819:agonists / Q000378:metabolism*; D012867:Skin / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects*; D013941:Thymine / Q000031:analogs & derivatives / Q000378:metabolism; D014466:Ultraviolet Rays; D014498:Uracil / Q000031:analogs & derivatives / Q000378:metabolism
D016207:Cytokines; D011743:Pyrimidines; D017382:Reactive Oxygen Species; C093681:isodialuric acid; C071023:2,6-diamino-4-hydroxy-5-formamidopyrimidine; C029389:thymine glycol; C039544:4,6-diamino-5-N-formamidopyrimidine; C024829:8-hydroxyguanine; D014498:Uracil; D006147:Guanine; D045647:DNA Glycosylases; C481347:Neil1 protein, mouse; C485990:Ogg1 protein, mouse; D013941:Thymine
DNA base excision repair; DNA glycosylases; Oxidatively-induced DNA base damage; UV-induced inflammation