Linking cancer cell metabolic reprogramming to the DNA repair mechanism

将癌细胞代谢重编程与 DNA 修复机制联系起来

基本信息

批准号：
8879428
负责人：
Roger A Greenberg
金额：
$ 17.4万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-04-01 至 2017-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8879428
关键词：
ATP Citrate (pro-S)-Lyase Acetyl Coenzyme A Acetylation Adverse effects Affect Anabolism BRCA1 gene Biological Assay Cancer Etiology Carbon Cell Cycle Cell Survival Cells Chromosome abnormality DNA Damage DNA Double Strand Break DNA Modification Process DNA Repair DNA Repair Pathway DNA repair protein Data Development Double Strand Break Repair Enzymes Epigenetic Process Equilibrium Fatty Acids G2 Phase Genome Stability Genomic Instability Glucose Growth Histone Acetylation Histone H4 Ionizing radiation Joints Link Lipids Lysine Mediating Metabolic Metabolic Control Metabolism Mutation Nonhomologous DNA End Joining Nuclear Oncogenes Oncogenic PARP inhibition Pathway interactions Play Predisposition Process Production Proteins Regulation Role S Phase STK11 gene Signal Transduction Site Source Testing Therapeutic cancer cell chemotherapeutic agent chemotherapy chromatin immunoprecipitation chromatin modification cytotoxic genome integrity glucose uptake histone modification homologous recombination improved inhibitor/antagonist novel novel strategies p53-binding protein 1 public health relevance repaired response

项目摘要

DESCRIPTION (provided by applicant): Metabolism is extensively rewired in cancer cells to support biosynthesis, growth, and proliferation. It has recently become apparent that many histone and DNA modifications are sensitive to cellular metabolic state. Histone acetylation is a dynamic chromatin modification, and global levels of histone acetylation are responsive to availability of the metabolite acetyl-CoA. However, the functional significance of metabolic control of histone acetylation remains poorly understood. The Wellen lab has recently shown that oncogenic activation of the PI3K-Akt pathway in cancer cells promotes acetyl-CoA production and elevated histone acetylation levels, indicating that normal metabolic controls on histone acetylation are disrupted in cancer cells. Extensive chromatin modifications, including histone acetylation, play crucial roles in the regulation of DNA repair. The Greenberg lab has recently shown that acetylation of histone H4 lysine 16 (H4K16ac) at sites of DNA double strand breaks (DSBs) plays a key role in recruitment of DNA repair proteins such as BRCA1 and utilization of DNA repair mechanisms. DSBs are repaired either by homologous recombination (HR) or non-homologous end joining (NHEJ). HR deficiencies, such as occur with BRCA1/2 mutations, result in genome instability and are a major cause of cancer predisposition and response to emerging chemotherapies. Since histone acetylation is responsive to acetyl-CoA availability and acetyl-CoA metabolism is frequently deregulated in cancer cells, we postulated that acetyl-CoA might impact H4K16ac levels at DSB sites to modulate the DNA repair efficiency. Our preliminary data shows that manipulation of nuclear-cytoplasmic acetyl-CoA levels by silencing the metabolic enzyme ATP-citrate lyase (ACLY) indeed impacts the recruitment of repair proteins to DSB sites, with recruitment of pro-NHEJ factor 53BP1 favored over pro-HR BRCA1 upon ACLY silencing. In this R21 application, we propose to test the hypothesis that oncogene-driven glucose uptake and acetyl- CoA production impact the acetylation state at DSBs and modulate the response to DNA damaging agents. We will pursue this hypothesis by first testing whether acetyl-CoA availability is indeed a critical determinant o DNA repair mechanism by affecting the balance of HR and NHEJ factors at DSBs. We will then examine the influence of altered acetyl-CoA metabolism mediated by the PI3K-Akt and LKB1-AMPK-ACC1 pathways on the DNA repair mechanism. This study has potential to identify previously unrecognized links between cellular metabolism and the DNA damage response and to identify new approaches to sensitize cells to chemotherapeutics.

描述（由申请人提供）：癌细胞中的代谢被广泛重新连接以支持生物合成、生长和增殖，最近发现许多组蛋白和 DNA 修饰对细胞代谢状态敏感。组蛋白乙酰化是一种动态染色质修饰。组蛋白乙酰化的整体水平对代谢物乙酰辅酶A的可用性有反应，然而，组蛋白乙酰化代谢控制的功能意义仍然知之甚少。 Wellen 实验室最近表明，癌细胞中 PI3K-Akt 通路的致癌激活会促进乙酰辅酶 A 的产生并升高组蛋白乙酰化水平，这表明癌细胞中组蛋白乙酰化的正常代谢控制被破坏，包括组蛋白乙酰化、 Greenberg 实验室最近表明，组蛋白 H4 赖氨酸 16 的乙酰化在 DNA 修复的调节中发挥着至关重要的作用。 DNA 双链断裂 (DSB) 位点的 H4K16ac (H4K16ac) 在 DNA 修复蛋白（例如 BRCA1）的募集和利用 DNA 修复机制通过同源重组 (HR) 或非同源末端连接进行修复方面发挥着关键作用。 HR 缺陷（例如 BRCA1/2 突变）会导致基因组不稳定，并且是癌症易感性和对新出现的化疗反应的主要原因。由于乙酰化对乙酰辅酶 A 的可用性有反应，并且癌细胞中乙酰辅酶 A 代谢经常失调，因此我们推测乙酰辅酶 A 可能会影响 DSB 位点的 H4K16ac 水平，从而调节 DNA 修复效率。通过沉默代谢酶 ATP-柠檬酸裂解酶 (ACLY) 来降低乙酰辅酶 A 水平确实会影响修复蛋白向 DSB 位点的募集， ACLY 沉默后，NHEJ 因子 53BP1 前体比 HR BRCA1 前体更受青睐在此 R21 应用中，我们建议检验致癌基因驱动的葡萄糖摄取和乙酰辅酶 A 产生影响 DSB 乙酰化状态并调节对 DNA 的反应的假设。我们将首先通过影响 HR 和 NHEJ 因子的平衡来检验乙酰辅酶 A 的可用性是否确实是 DNA 修复机制的关键决定因素。然后，我们将检查 PI3K-Akt 和 LKB1-AMPK-ACC1 途径介导的乙酰辅酶 A 代谢改变对 DNA 修复机制的影响。这项研究有可能确定细胞代谢和 DNA 损伤反应之间以前未被认识的联系。并确定使细胞对化疗药物敏感的新方法。