Regulation of Ionizing Radiation-Induced DNA Damage Response

电离辐射诱导的 DNA 损伤反应的调节

基本信息

批准号：
9325472
负责人：
Xiaochun Yu
金额：
$ 38.25万
依托单位：
BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-05-01 至 2019-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9325472
关键词：
Apoptosis Architecture Binding C-terminal Cancer Patient Cell Cycle Arrest Cells DNA Damage DNA Double Strand Break DNA Repair DNA damage checkpoint DNA lesion Defect Double Strand Break Repair Event Evolution FHA Domain Functional disorder Future Gene Mutation Gene Silencing Half-Life Histones Ionizing radiation Knockout Mice Lead Malignant Neoplasms Mammals Mediating Molecular Mus Mutation N-terminal Normal Cell PI3 gene PRKDC gene Pathway interactions Phosphorylation Phosphotransferases Play Poly Adenosine Diphosphate Ribose Proteins Radiation Induced DNA Damage Radiation induced double strand break Radiation therapy Recruitment Activity Regulation Risk Role Signal Transduction Site Solid Solid Neoplasm System T-Cell Lymphoma Tertiary Protein Structure Testing Therapeutic Tumor Markers Tumor Suppression Tumor Suppressor Proteins Ubiquitin Ubiquitination Variant cancer cell cancer prevention chromatin remodeling experimental study in vivo insight killings novel paralogous gene poly ADP-ribose glycohydrolase public health relevance response tumor tumorigenesis ubiquitin-protein ligase

项目摘要

DESCRIPTION (provided by applicant): Ionizing radiation (IR) is an important therapeutic approach to kill cancer cells by inducing DNA double strand breaks (DSBs) that lead to cell apoptosis. However, normal cells are protected from IR-induced cell lethality by a DNA damage response system including DNA damage checkpoint activation and DNA damage repair. Thus, it is important for understanding the molecular mechanism of IR-induced DNA damage response, so that more effective radiation therapy can be achieved to treat cancer patients. In response to IR-induced DSBs, a signal cascade initiated by a group of PI3-like kinases including ATM, ATR and DNAPK arrests cell cycle progression and facilitates DNA damage repair. Besides these protein phosphorylation events, we and others recently found that a protein ubiquitination cascade is involved in DSBs response. These ubiquitination events are activated by RNF8, a Ring domain E3 ligase. Following the initial RNF8-dependent ubiquitination, the ubiquitin (ub) signals are amplified by a group of downstream ub E3 ligases, such as RNF168, RNF169, RAD18, and HERC2. These ubiquitination events regulate chromatin remodeling and other histone marks, which facilitates DNA damage repair by recruiting down-stream DNA damage repair factors to DSBs. In this application, we plan to continue studying the IR-induced protein ubiquitination cascade by focusing on CHFR, a paralog of RNF8 in mammals. The domain architecture of CHFR and RNF8 is very similar. Both of them contain an N-terminal FHA domain that is likely to recognize phospho-Thr, and a Ring domain that interacts Ubc13 or UbcH5C to catalyze histone ubiquitination in response to DSBs. Lacking these two E3 ub ligases additively suppress DNA damage response and induces tumorigenesis in vivo. Different from RNF8, CHFR contains a C-terminal PBZ motif that binds poly(ADP-ribose) (PAR), which facilitates the fast recruitment of CHFR to DNA damage sites and mediates the ubiquitinaition of PARP1. Moreover, Chfr-deficient mice are tumor prone, and cancer-associated CHFR gene mutations have been identified in primary solid tumors. These lines of evidence suggest that CHFR is an important tumor suppressor. Thus, in this application, we plan to examine the molecular mechanism of CHFR in IR-induced DNA damage response and tumor suppression.

描述（由申请人提供）：电离辐射（IR）是通过诱导导致细胞凋亡的DNA双链断裂（DSB）杀死癌细胞的重要治疗方法。然而，正常细胞通过包括DNA损伤响应系统（包括DNA损伤检查点激活和DNA损伤修复）保护了IR诱导的细胞致死性。因此，重要的是了解IR诱导的DNA损伤反应的分子机制，因此可以实现更有效的放射治疗来治疗癌症患者。响应IR诱导的DSB，由一组PI3样激酶（包括ATM，ATR和DNAPK）引发的信号级联反应可阻止细胞周期的进展并促进DNA损伤修复。除了这些蛋白质磷酸化事件外，我们和其他人最近发现蛋白质泛素化级联反应涉及DSBS反应。这些泛素化事件被RNF8（一个环域E3连接酶）激活。遵循最初的RNF8依赖性泛素化，泛素（UB）信号被一组下游UB E3连接酶放大，例如RNF168，RNF169，RAD18和HERC2。这些泛素化事件调节染色质重塑和其他组蛋白标记，从而通过向DSB募集下游DNA损伤修复因子来促进DNA损伤修复。在此应用中，我们计划通过关注CHFR（哺乳动物的RNF8的副产品CHFR）来继续研究IR诱导的蛋白质泛素化级联反应。 CHFR和RNF8的域结构非常相似。它们俩都包含一个可能识别磷酸化的N端FHA结构域，以及与UBC13或UBCH5C相互作用的环域以催化对DSB的组蛋白泛素化。缺乏这两个E3 UB连接酶加上抑制DNA损伤反应并在体内诱导肿瘤发生。与RNF8不同，CHFR包含结合聚（ADP-核糖）（PAR）的C端PBZ基序，该基序促进了CHFR快速募集到DNA损伤位点并介导PARP1的ubiquitinaention。此外，CHFR缺陷型小鼠易于肿瘤，与癌症相关的CHFR基因突变已在原发性实体瘤中鉴定出来。这些证据表明，CHFR是重要的肿瘤抑制剂。因此，在此应用中，我们计划在IR诱导的DNA损伤反应和抑制肿瘤中检查CHFR的分子机制。