DDB2, an essential mediator of premature senescence.
Reactive oxygen species (ROS) is critical for premature senescence, a process significant in tumor suppression and cancer therapy. Here, we reveal a novel function of the nucleotide excision repair protein DDB2 in the accumulation of ROS in a manner that is essential for premature senescence. DDB2-deficient cells fail to undergo premature senescence induced by culture shock, exogenous oxidative stress, oncogenic stress, or DNA damage. These cells do not accumulate ROS following DNA damage. The lack of ROS accumulation in DDB2 deficiency results from high-level expression of the antioxidant genes in vitro and in vivo. DDB2 represses antioxidant genes by recruiting Cul4A and Suv39h and by increasing histone-H3K9 trimethylation. Moreover, expression of DDB2 also is induced by ROS. Together, our results show that, upon oxidative stress, DDB2 functions in a positive feedback loop by repressing the antioxidant genes to cause persistent accumulation of ROS and induce premature senescence.
Roy
Nilotpal
N
Center of Molecular Biology of Oral Diseases (M/C 860), College of Dentistry, Cancer Center, University of Illinois at Chicago, 801 S. Paulina Ave., Chicago, IL 60612, USA.
Stoyanova
Tanya
T
Dominguez-Brauer
Carmen
C
Park
Hyun Jung
HJ
Bagchi
Srilata
S
Raychaudhuri
Pradip
P
D020823:ADP-Ribosylation Factor 1 / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002374:Catalase / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000502:physiology*; D042002:Chromatin Assembly and Disassembly; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005347:Fibroblasts / Q000166:cytology / Q000502:physiology; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D018384:Oxidative Stress / Q000502:physiology*; D012313:RNA / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism; D014018:Tissue Distribution
D004268:DNA-Binding Proteins; C496850:Ddb2 protein, mouse; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D012313:RNA; D002374:Catalase; D013482:Superoxide Dismutase; D020823:ADP-Ribosylation Factor 1