Analysis of 53BP1 function in DNA Damage-signaled pathway and Tumorigenesis

53BP1在DNA损伤信号通路与肿瘤发生中的功能分析

基本信息

批准号：
7789617
负责人：
Junjie Chen
金额：
$ 29.35万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-05-09 至 2012-03-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): The maintenance of genomic integrity following DMA damage depends on the coordination of the cell cycle checkpoint controls and DNA repair. Increasing evidence suggests that the integrity of the DMA damage- signaling pathway is essential for the prevention of neoplastic transformation, since many proteins involved in this pathway are frequently mutated in human cancers. Thus, a better understanding the DNA damage-signaling pathway will help us elucidate the pathway that is critical for the maintenance of genomic integrity and for the prevention of tumorigenesis. 53BP1 (p53-binding protein 1) was first identified in a yeast two-hybrid screen as a protein that interacts with the central DMA-binding domain of p53. In the last few years, we and others have demonstrated that 53BP1 is involved early in DNA damage-signaling pathway and plays a critical role in DNA damage checkpoint control and DNA repair. Moreover, we have shown that loss of 53BP1 greatly facilitates tumorigenesis in vivo, supporting that proper DNA damage responses are essential for the maintenance of genomic stability and cancer prevention. However, the mechanisms by which 53BP1 operates and the complexity of the DNA damage responses have not yet been adequately addressed. In this proposal, we will study the multiple functional motifs in 53BP1 in Specific Aim 1. The goal here is to elucidate how 53BP1 acts as a DNA damage mediator through its interactions with various upstream and downstream protein components involved in DNA damage pathways. In Specific Aim 2, we will explore the potential redundant functions between 53BP1 and another mediator of DNA damage checkpoint MDC1. 53BP1 rapidly relocalizes to the sites of DNA breaks. Recent studies suggest that a protein methyltransferase Dot1-dependent Lys-79 methylation of histone H3 is required for this initial recruitment of 53BP1. In Specific Aim 3, we will generate Dot1 knockout mice and explore the role of Dot1 and Dot1 -dependent H3 methylation in the regulation of DNA damage responses including 53BP1 localization. Collectively, these genetic, structural and biochemical analyses of 53BP1 protein will reveal, at molecular details, how 53BP1 participates in DNA damage responses and contributes to tumor suppression.

描述（由申请人提供）：DMA损伤后基因组完整性的维持取决于细胞周期检查点控制和DNA修复的协调。越来越多的证据表明，DMA损伤信号传导途径的完整性对于预防肿瘤转化至关重要，因为在人类癌症中经常会突变参与该途径的蛋白质。因此，更好地理解DNA损伤信号途径将有助于我们阐明对维持基因组完整性和预防肿瘤发生至关重要的途径。首先在酵母双杂交筛选中鉴定出53BP1（p53结合蛋白1）是与p53中央DMA结合结构域相互作用的蛋白质。在过去的几年中，我们和其他人证明了53BP1早期参与了DNA损伤信号途径，并且在DNA损伤检查点控制和DNA修复中起着至关重要的作用。此外，我们已经表明，53BP1的损失极大地促进了体内肿瘤发生，这支持适当的DNA损伤反应对于维持基因组稳定性和预防癌症至关重要。但是，53BP1运行的机制以及DNA损伤反应的复杂性尚未得到充分解决。在此提案中，我们将在特定目标1中研究53BP1中的多个功能基序。此处的目标是通过与各种与DNA损害途径相关的上游和下游蛋白质成分的相互作用来阐明53BP1如何充当DNA损伤介质。在特定的目标2中，我们将探索53BP1与DNA损伤检查点MDC1的另一个介体之间的潜在冗余功能。 53BP1迅速迁移到DNA断裂部位。最近的研究表明，这种蛋白甲基转移酶DOT1依赖性LYS-79组蛋白H3的甲基化是该最初募集的53BP1所必需的。在特定的目标3中，我们将生成DOT1敲除小鼠，并探讨DOT1和DOT1依赖性H3甲基化在包括53BP1定位的DNA损伤反应中的作用。总的来说，这些53BP1蛋白的遗传，结构和生化分析将在分子细节上揭示53BP1如何参与DNA损伤反应并有助于抑制肿瘤。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

53BP1 is required for class switch recombination.

DOI：
10.1083/jcb.200403021
发表时间：
2004-05-24
期刊：
The Journal of cell biology
影响因子：
0
作者：
Ward IM;Reina-San-Martin B;Olaru A;Minn K;Tamada K;Lau JS;Cascalho M;Chen L;Nussenzweig A;Livak F;Nussenzweig MC;Chen J
通讯作者：
Chen J