ATF3 Regulation of Histone Acetylation in Genome Maintenance

ATF3 在基因组维护中对组蛋白乙酰化的调节

• 批准号: 10374867
• 负责人: Chunhong Yan
• 金额: $ 34.52万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-10 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10374867
• 关键词: Acetylation; Address; Binding; Cell physiology; Cells; Chemotherapy and/or radiation; Chromatin; Chromatin Structure; DNA; DNA Damage; DNA Double Strand Break; DNA Repair; DNA Repair Pathway; Data; Development; Double Strand Break Repair; EP300 gene; Event; Evolution; Excision; Gamma-H2AX; Genes; Genetic Transcription; Genetically Engineered Mouse; Genome; Genome Stability; Goals; Hematopoietic; Hematopoietic stem cells; Histone Acetylation; Histone H3; Histones; Immunoglobulin Class Switching; Immunoglobulin Switch Recombination; Impairment; Knockout Mice; Lead; Lymphomagenesis; Maintenance; Malignant - descriptor; Malignant Neoplasms; Mediating; Modeling; Mus; Nonhomologous DNA End Joining; Nucleosomes; Outcome; Pathway interactions; Persons; Physiological; Play; Proteins; Publishing; Radiation; Radiation therapy; Reader; Regulation; Relaxation; Research; Role; Site; Stress; TP53 gene; Testing; Treatment outcome; Tumor Suppression; Tumor Suppressor Proteins; Ubiquitination; activating transcription factor 3; anti-cancer; ataxia telangiectasia mutated protein; biomarker identification; cancer cell; cancer therapy; chemotherapeutic agent; chemotherapy; gamma irradiation; genome integrity; genotoxicity; histone acetyltransferase; improved; mouse model; novel; novel strategies; p53-binding protein 1; patient response; predictive marker; prevent; radiation response; recruit; repaired; response; sensor; tumorigenesis

Project Summary A better understanding of the DNA damage response (DDR) is of utmost importance because this evolutionally-conserved genome-maintaining mechanism not only serves as an anti-cancer barrier, but influences efficacies of radiation therapy and chemotherapy that mainly kill cancer cells by inducing DNA damage. Whereas DNA is embedded in highly-ordered chromatin, DNA damage promptly induces chromatin alterations at sites of damage. One such early change, histone acetylation catalyzed by histone acetyltransferases Tip60 and p300/CBP, not only can promote chromatin access to the DNA-repair machinery, but can regulate DNA-repair pathway choice. As histone acetylation has emerged as a principal mechanism for coordinating DDR, it is of significance to identify genes that can regulate this event upon DNA damage. Activating transcription factor 3 (ATF3) is a stress sensor commonly induced by DNA-damaging agents. We have demonstrated that ATF3 can activate the tumor suppressor p53 while promoting Tip60-mediated activation of the major DDR kinase ATM. We also found that ATF3 is required for genome maintenance and the suppression of spontaneous tumorigenesis in mice. Whereas these results support that ATF3 plays an indispensable role in the DNA damage response, what is currently unknown is whether ATF3 can also actively regulate chromatin dynamics and DNA repair independent of its regulation on p53 and Tip60. The objective of this application is to address this question, and to determine the role of ATF3 in the regulation of DNA repair at the chromatin level. Formulated on the basis of compelling preliminary data, the central hypothesis is that ATF3 recruited to sites of DNA damage promotes p300/CBP to acetylate H3 facilitating the loading of repair proteins for non-homologous end-joining (NHEJ). To test this hypothesis, we will determine how ATF3 is recruited to DSBs and promotes p300/CBP-catalyzed histone acetylation at DSBs (Aim 1). We will also delineate how histone acetylation regulated by ATF3 alters chromatin structure and facilitates the recruitments of NHEJ factors (Aim 2). Lastly, we will also use the IR-induced lymphomagenesis mouse model to assess the functional significance of our novel findings (Aim 3). Completion of the proposed research is expected to define a novel role that ATF3 plays in genome maintenance, and discover novel mechanisms by which the early chromatin response to DNA damage is regulated.

项目摘要 更好地了解DNA损伤反应（DDR）至关重要，因为这 进化上保守的基因组维持机制不仅作为抗癌屏障， 影响主要通过诱导DNA杀伤癌细胞的放疗和化疗的疗效 损害而DNA是嵌入在高度有序的染色质，DNA损伤迅速诱导染色质 在受损部位进行改建。其中一个早期的变化，组蛋白乙酰化催化的组蛋白 乙酰转移酶Tip 60和p300/CBP不仅可以促进染色质进入DNA修复机制， 但可以调节DNA修复途径的选择。由于组蛋白乙酰化已成为一种主要的机制， 与DDR相协调，鉴定能够在DNA损伤时调节该事件的基因具有重要意义。 转录激活因子3（Activating transcription factor 3，ATF 3）是一种由DNA损伤因子诱导的应激感受器。我们 已经证明，ATF 3可以激活肿瘤抑制基因p53，同时促进Tip 60介导的 主要DDR激酶ATM的激活。我们还发现ATF 3是基因组维持所必需的， 抑制小鼠自发性肿瘤发生。尽管这些结果支持ATF 3在细胞中起作用， 在DNA损伤反应中不可或缺的作用，目前尚不清楚的是ATF 3是否也可以积极地 调节染色质动力学和DNA修复，而不依赖于其对p53和Tip 60的调节。的目标 本申请旨在解决这一问题，并确定ATF 3在DNA修复调控中的作用。 染色质水平。根据令人信服的初步数据，中心假设是， ATF 3募集到DNA损伤位点促进p300/CBP乙酰化H3，促进修复的加载 非同源末端连接蛋白（NHEJ）。为了验证这一假设，我们将确定ATF 3是如何 募集到DSB并促进DSB处p300/CBP催化的组蛋白乙酰化（目的1）。我们还将 描述由ATF 3调控的组蛋白乙酰化如何改变染色质结构并促进细胞的募集 NHEJ因素（目标2）。最后，我们还将使用IR诱导的淋巴瘤发生小鼠模型来评估 我们新发现的功能意义（目的3）。预计完成拟议的研究将确定 ATF 3在基因组维护中发挥的新作用，并发现了新的机制， 染色质对DNA损伤的反应受到调节。