Transcriptional Repression of High-Mobility Group Box 2 by p21 in Radiation-Induced Senescence
Hyun-Kyung Kim1,2,6, Mi Ae Kang1,6, Mi-Sook Kim3, Young-Joo Shin4, Sung-Gil Chi2, and Jae-Hoon Jeong1,5,*
1Division of Applied Radiation Bioscience, Korea Institute of Radiological and Medical Sciences, Seoul 01812, Korea, 2Department of Life Sciences, Korea University, Seoul 02841, Korea, 3Department of Radiation Oncology, Korea Institute of Radiological and Medical Sciences, Seoul 01812, Korea, 4Department of Radiation Oncology, Inje University Sanggye Paik Hospital, Seoul 01757, Korea, 5Radiological & Medico-Oncological Sciences, Korea University of Science and Technology, Daejeon 34113, Korea, 6These authors contributed equally to this work.
Received November 6, 2017; Revised January 26, 2018; Accepted January 28, 2018.; Published online February 28, 2018.
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High mobility group box 2 (HMGB2) is an abundant, chromatin-associated, non-histone protein involved in transcription, chromatin remodeling, and recombination. Recently, the HMGB2 gene was found to be significantly downregulated during senescence and shown to regulate the expression of senescent-associated secretory proteins. Here, we demonstrate that HMGB2 transcription is repressed by p21 during radiation-induced senescence through the ATM-p53-p21 DNA damage signaling cascade. The loss of p21 abolished the downregulation of HMGB2 caused by ionizing radiation, and the conditional induction of p21 was sufficient to repress the transcription of HMGB2. We also showed that the p21 protein binds to the HMGB2 promoter region, leading to sequestration of RNA polymerase and transcription factors E2F1, Sp1, and p300. In contrast, NF-Y, a CCAAT box-binding protein complex, is required for the expression of HMGB2, but NF-Y binding to the HMGB2 promoter was unaffected by either radiation or p21 induction. A proximity ligation assay results confirmed that the chromosome binding of E2F1 and Sp1 was inhibited by p21 induction. As HMGB2 have been shown to regulate premature senescence by IR, targeting the p21-mediated repression of HMGB2 could be a strategy to overcome the detrimental effects of radiation-induced senescence.
Keywords: HMGB2, p21, radiation, senescence, transcription repression

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