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Investigation of a Novel Role for RNA Binding Proteins in DNA Repair

RNA 结合蛋白在 DNA 修复中的新作用的研究

基本信息

批准号：
8472446
负责人：
William S. Dynan
金额：
$ 25.63万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-07-26 至 2015-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8472446
关键词：
Adenosine Area Biogenesis Biology Cells Cellular biology Chromosome Pairing Clinical Complex Core Protein DNA DNA Damage DNA Double Strand Break DNA Repair DNA Repair Pathway Deposition Distant Double Strand Break Repair Family Family member Functional RNA Gene Expression Gene Expression Regulation Human Inosine Investigation Ionizing radiation Lesion Link Mammalian Cell Mediating Mediator of activation protein Messenger RNA Modeling Molecular Nature Normal tissue morphology Nuclear Structure Nucleic Acids Nucleoplasm Pathway interactions Phenotype Post-Translational Protein Processing Protein Family Proteins RNA RNA-Binding Proteins Radiation Radiation Tolerance Radiation therapy Radiation-Sensitizing Agents Relative (related person)Reliance Research Role Site Structure System Testing Therapeutic Untranslated RNA Work genetic manipulation homologous recombination improved innovation interest member novel protein function public health relevance radiation resistance reconstitution repaired research study response scaffold tumor

项目摘要

DESCRIPTION (provided by applicant): This is a proposal to investigate proteins that contribute to the efficiency and accuracy of DNA double-strand break (DSB) repair. Ionizing radiation deposits energy along discrete tracks, resulting in clustered DNA damage and DSBs. The ability to repair these signature lesions is a major determinant of radiation sensitivity and resistance in both normal tissue and tumors. Manipulation of DNA repair pathways therefore affords a promising approach for improving the efficacy of radiotherapy. Recent work provides evidence for the novel involvement of a small family of human RNA binding proteins in DSB repair. These proteins are core components of paraspeckles, which are nuclear structures that are organized around a long noncoding RNA scaffold and that regulate gene expression by retaining adenosine-to- inosine hyper-edited mRNAs. Separate experiments indicate, however, that these proteins participate in both homologous recombination and nonhomologous end joining, which are the two main pathways of DSB repair in human cells. The three members of the family in humans-PSF, p54nrb, and PSPC1-rapidly relocalize to sites of induced DNA damage, suggesting the existence of a molecular switch that controls RNA versus DNA interaction. The hypothesis to be tested is that PSF and its partners are mediators of gene regulation and DNA repair that switch rapidly between RNA and DNA interaction modes following the induction of DNA damage. A unifying theme may be reliance on an intrinsic ability of PSF and its partners to promote pairing of distant nucleic acid segments. The first specific aim will be to test a prediction that a PSF7p54nrb complex promotes juxtaposition of opposing DNA ends in a loop structure. The second will be to examine repair functions of PSF and its partners more broadly using genetic manipulation of human cells. The third will focus directly on how PSF and its partners switch between RNA biogenesis and DSB repair modes and will investigate the therapeutic applicability of this mechanism. The proposed research is innovative, because the primary sequence and domain structure of PSF, p54nrb, and PSPC1 are unlike any previously characterized DSB repair proteins. The work is scientifically significant, because it explores a previously unsuspected link between DSB repair and the biology of non-coding RNAs, which is an interesting and topical area in cell biology. Finally, the work has potential clinical and translational impact, because of the possibility that therapeutic RNAs might be developed to influence switching between RNA biogenesis and DNA repair modes to alter clinical radiation response.

描述（由申请人提供）：这是一项研究有助于DNA双链断裂（DSB）修复效率和准确性的蛋白质的提案。电离辐射使能量沿着离散轨迹沉积，导致成簇的DNA损伤和DSB。修复这些特征性病变的能力是正常组织和肿瘤中辐射敏感性和抗性的主要决定因素。因此，DNA修复途径的操纵提供了一个有前途的方法，提高放射治疗的疗效。最近的工作提供了一个小家族的人RNA结合蛋白在DSB修复的新参与的证据。这些蛋白质是paraspeckles的核心组成部分，paraspeckles是围绕长的非编码RNA支架组织的核结构，并通过保留腺苷到肌苷的超编辑mRNA来调节基因表达。然而，单独的实验表明，这些蛋白质参与同源重组和非同源末端连接，这是人类细胞中DSB修复的两个主要途径。人类中的三个家族成员-PSF、p54 nrb和PSPC 1-迅速重新定位于诱导DNA损伤的位点，表明存在控制RNA与DNA相互作用的分子开关。要测试的假设是，PSF和它的合作伙伴是基因调控和DNA修复的介质，在诱导DNA损伤后，在RNA和DNA相互作用模式之间迅速切换。一个统一的主题可能是依赖于PSF及其伙伴的内在能力，以促进远距离核酸片段的配对。第一个具体的目标将是测试一个预测，即一个PSF 7 p54 nrb复合物促进并列的相对DNA末端的环结构。第二个将是更广泛地使用人类细胞的遗传操作来检查PSF及其伙伴的修复功能。第三个将直接关注PSF及其合作伙伴如何在RNA生物合成和DSB修复模式之间切换，并将研究这种机制的治疗适用性。这项研究具有创新性，因为PSF、p54 nrb和PSPC 1的一级序列和结构域结构与任何先前表征的DSB修复蛋白不同。这项工作具有科学意义，因为它探索了DSB修复与非编码RNA生物学之间先前未被怀疑的联系，这是细胞生物学中一个有趣和热门的领域。最后，这项工作具有潜在的临床和翻译影响，因为可能开发治疗性RNA来影响RNA生物发生和DNA修复模式之间的转换，以改变临床辐射反应。

项目成果

期刊论文数量（12）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Involvement of p54(nrb), a PSF partner protein, in DNA double-strand break repair and radioresistance.

DOI：
10.1093/nar/gkp741
发表时间：
2009-11
期刊：
Nucleic acids research
影响因子：
14.9
作者：
Li S;Kuhne WW;Kulharya A;Hudson FZ;Ha K;Cao Z;Dynan WS
通讯作者：
Dynan WS

Terminal DNA structure and ATP influence binding parameters of the DNA-dependent protein kinase at an early step prior to DNA synapsis.

DOI：
10.1093/nar/gkj504
发表时间：
2006
期刊：
NUCLEIC ACIDS RESEARCH
影响因子：
14.9
作者：
Jovanovic, M;Dynan, WS
通讯作者：
Dynan, WS

ATRIP Deacetylation by SIRT2 Drives ATR Checkpoint Activation by Promoting Binding to RPA-ssDNA.

DOI：
10.1016/j.celrep.2016.01.018
发表时间：
2016-02-16
期刊：
Cell reports
影响因子：
8.8
作者：
Zhang H;Head PE;Daddacha W;Park SH;Li X;Pan Y;Madden MZ;Duong DM;Xie M;Yu B;Warren MD;Liu EA;Dhere VR;Li C;Pradilla I;Torres MA;Wang Y;Dynan WS;Doetsch PW;Deng X;Seyfried NT;Gius D;Yu DS
通讯作者：
Yu DS

SFPQ•NONO and XLF function separately and together to promote DNA double-strand break repair via canonical nonhomologous end joining.