Subtelomeric p53 Binding Prevents Accumulation of DNA Damage at Human Telomeres

Telomeres and tumor suppressor protein TP53 (p53) function in genome protection, but a direct role of p53 at telomeres has not yet been described. Here, we have identified non-canonical p53 binding sites within the human subtelomeres that suppress the accumulation of DNA damage at telomeric repeat DNA. These non-canonical subtelomeric p53 binding sites conferred transcription enhancer-like functions that include an increase in local histone H3K9 and H3K27 acetylation and stimulation of subtelomeric transcripts, including telomere-repeat containing RNA (TERRA). p53 suppressed formation of telomere-associated ?H2AX and prevented telomere DNA degradation in response to DNA damage stress. Our findings indicate that p53 provides a direct chromatin-associated protection to human telomeres, as well as other fragile genomic sites. We propose that p53-associated chromatin modifications enhance local DNA repair or protection to provide a previously unrecognized tumor suppressor function of p53. Overall design: p53 binding was analyzed by ChIP-Seq in HCT116 cells treated with camptothecin or untreated control.

端粒（Telomeres）与肿瘤抑制蛋白TP53（p53）均参与基因组保护过程，但p53在端粒位点的直接作用迄今尚未被阐明。本研究于人类亚端粒区域（human subtelomeres）内鉴定出一类非经典p53结合位点（non-canonical p53 binding sites），该位点可抑制端粒重复DNA（telomeric repeat DNA）区域的DNA损伤（DNA damage）积累。此类非经典亚端粒p53结合位点具备类转录增强子的功能特性，具体包括提升局部组蛋白H3K9与H3K27乙酰化（histone H3K9 and H3K27 acetylation）水平，以及激活包括含端粒重复序列的RNA（TERRA）在内的亚端粒转录本的表达。在DNA损伤应激（DNA damage stress）条件下，p53可抑制端粒相关γH2AX的形成，并阻断端粒DNA的降解。本研究结果证实，p53可为人类端粒及其他脆弱基因组位点提供直接的染色质关联保护作用。我们提出，p53介导的染色质修饰（chromatin modifications）可增强局部DNA修复（DNA repair）或保护能力，由此揭示了p53此前未被发现的肿瘤抑制功能。实验设计概要：采用染色质免疫共沉淀测序（ChIP-Seq）技术，分析经喜树碱（camptothecin）处理与未处理的HCT116细胞中的p53结合情况。