Transcriptional Repression of High-Mobility Group Box 2 by p21 in Radiation-Induced Senescence

• Published in: Molecules and cells Vol. 41; no. 4; pp. 362 - 372
• Main Authors: Kim, Hyun-Kyung, Kang, Mi Ae, Kim, Mi-Sook, Shin, Young-Joo, Chi, Sung-Gil, Jeong, Jae-Hoon
• Format: Journal Article
• Language: English
• Published: United States Korean Society for Molecular and Cellular Biology 30.04.2018; 한국분자세포생물학회
• Subjects: Adenocarcinoma - genetics; Adenocarcinoma - metabolism; Adenocarcinoma - pathology; Adenocarcinoma - radiotherapy; Adenocarcinoma of Lung; Ataxia Telangiectasia Mutated Proteins - genetics; Ataxia Telangiectasia Mutated Proteins - metabolism; Cell Line, Tumor; Cellular Senescence - physiology; Cellular Senescence - radiation effects; Colorectal Neoplasms - genetics; Colorectal Neoplasms - metabolism; Colorectal Neoplasms - pathology; Colorectal Neoplasms - radiotherapy; Cyclin-Dependent Kinase Inhibitor p21 - genetics; Cyclin-Dependent Kinase Inhibitor p21 - metabolism; DNA Damage; Down-Regulation; Fibroblasts - metabolism; Fibroblasts - pathology; Fibroblasts - radiation effects; HMGB2 Protein - genetics; HMGB2 Protein - metabolism; HT29 Cells; Humans; Lung Neoplasms - genetics; Lung Neoplasms - metabolism; Lung Neoplasms - pathology; Lung Neoplasms - radiotherapy; Promoter Regions, Genetic; Radiotherapy; Transcription, Genetic; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism; 생물학; senescence; HMGB2; transcription repression; radiation; p21
• ISSN: 1016-8478; 0219-1032
• DOI: 10.14348/molcells.2018.2291

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.