ATM Function During V(D)J Recombination

V(D)J 重组期间的 ATM 功能

基本信息

  • 批准号:
    10317289
  • 负责人:
  • 金额:
    $ 37.13万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2008
  • 资助国家:
    美国
  • 起止时间:
    2008-12-02 至 2023-11-30
  • 项目状态:
    已结题

项目摘要

Abstract Lymphocyte antigen receptor gene assembly occurs through the V(D)J recombination reaction. This reaction is initiated when the RAG-1 and RAG-2 proteins, which form the RAG endonuclease, introduces two DNA double strand breaks (DSBs) at the border of two recombining gene segments and their associated V, D or J gene segments. This results in the formation of a coding end and a signal end at each DSB. The coding ends must be joined to form a coding join and the signal ends joined to form a signal join. Also, as a single individual can make up to 60,000,000 RAG DSBs in an hour in developing B and T cells, pathways must be in place to prevent un-repaired RAG DSBs from being aberrantly repaired, forming potentially transforming chromosomal deletions and translocations. The non-homologous end-joining pathway of DNA DSB repair joins DNA DSBs generated by RAG cleavage. NHEJ relies on four core NHEJ factors, XRCC4, DNA Ligase IV, Ku70 and Ku80. However, there are other non-core NHEJ factors that function during the NHEJ-mediated repair of RAG DSBs. For example, coding join formation relies on the ncNHEJ factor, Artemis, which is endonuclease that opens the hairpin-sealed coding ends generated by RAG cleavage. Artemis is not required for joining signal ends. In addition, there are other ncNHEJ factors that are not themselves required for RAG DSB repair, but that likely effect the efficiency of RAG DSB repair or function to prevent aberrant repair of RAG DSBs that are not joined efficiently. Identifying ncNHEJ factors has been challenging given that their deletion does not often lead to a demonstrable defect in the repair of RAG DSBs. However, recent studies have established that combined deficiencies of putative ncNHEJ factors can lead to demonstrable defects in RAG DSBs repair. This has been a powerful candidate-based approach for identifying several ncNHEJ factors and elucidating their mechanisms of action in NHEJ-mediated DSB repair and DNA damage responses (DDR). Indeed, using this type of approach, we have identified a novel ncNHEJ protein, modulator of retroviral infection (MRI), that binds through its N- and C-terminus to a functionally diverse set of NHEJ and DDR proteins. We believe that MRI functions as an adaptor during several steps of NHEJ-mediated repair of RAG DSBs and during the DDR to RAG DSBs. Here we propose a novel unbiased screening approach to identify the network of ncNHEJ factors that function during RAG DSB repair. We also propose to elucidate the mechanisms of action of these ncNHEJ factors focusing initially on the novel ncNHEJ factor, MRI, that we recently discovered that functions in RAG DSB repair. These studies will reveal novel activities required for the NHEJ-mediated repair of RAG DSBs. These activities will likely be generally relevant to NHEJ in other tissues and to our understanding to DNA repair defects that lead to genome evolution in cancers.
摘要 淋巴细胞抗原受体基因组装通过V(D)J重组反应发生。该反应 当形成RAG内切核酸酶的RAG-1和RAG-2蛋白引入两个DNA时, 在两个重组基因片段的边界处的双链断裂(DSB)及其相关的V、D或J 基因片段这导致在每个DSB处形成编码端和信号端。编码结束 必须连接以形成编码连接,并且信号端连接以形成信号连接。作为一个单一的 在发育中B和T细胞中,个体可以在一小时内形成多达60,000,000个RAG DSB, 防止未修复的RAG DSB被异常修复,形成潜在的转化 染色体缺失和易位。DNA双链断裂修复的非同源末端连接途径 连接由RAG切割产生的DNA DSB。NHEJ依赖于四个核心NHEJ因子:XRCC 4、DNA连接酶 四、Ku 70和Ku 80。然而,存在在NHEJ介导的细胞凋亡过程中起作用的其他非核心NHEJ因子。 修复RAG DSB。例如,编码连接形成依赖于ncNHEJ因子Artemis, 在一些实施方案中,RAG是一种打开由RAG切割产生的发夹密封的编码末端的核酸内切酶。阿耳忒弥斯不是必需的 用于连接信号端。此外,还有其他ncNHEJ因子本身不是RAG所需的 DSB修复,但这可能影响RAG DSB修复的效率或防止RAG异常修复的功能 没有有效连接的DSB。鉴定ncNHEJ因子具有挑战性,因为它们的缺失 通常不会导致RAG DSB修复的明显缺陷。但最近的研究 确定了假定的ncNHEJ因子的组合缺陷可导致RAG中的可证实的缺陷 DSB修复。这是一种强有力的基于候选人的方法,用于鉴定几种ncNHEJ因子, 阐明它们在NHEJ介导的DSB修复和DNA损伤应答(DDR)中的作用机制。 事实上,使用这种类型的方法,我们已经确定了一种新的ncNHEJ蛋白,逆转录病毒的调节剂, 感染(MRI),其通过其N-和C-末端结合至功能多样的NHEJ和DDR集合 proteins.我们认为MRI在NHEJ介导的RAG修复的几个步骤中起着适配器的作用 DSB和DDR到RAG DSB期间。在这里,我们提出了一种新的无偏筛选方法,以确定 在RAG DSB修复期间起作用的ncNHEJ因子的网络。我们亦建议澄清 这些ncNHEJ因子的作用机制最初集中在新的ncNHEJ因子,MRI,我们 最近发现在RAG DSB修复中起作用。这些研究将揭示新的活动所需的 NHEJ介导的RAG DSB修复。这些活动通常可能与其他组织中的NHEJ相关 以及我们对导致癌症基因组进化的DNA修复缺陷的理解。

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

BARRY P SLECKMAN其他文献

BARRY P SLECKMAN的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('BARRY P SLECKMAN', 18)}}的其他基金

INHIBITORS OF COMPENSATORY NHEJ PATHWAYS
NHEJ 代偿途径的抑制剂
  • 批准号:
    8486208
  • 财政年份:
    2013
  • 资助金额:
    $ 37.13万
  • 项目类别:
ATM FUNCTION DURING V(D)J RECOMBINATION
V(D)J 重组期间的 ATM 功能
  • 批准号:
    7879173
  • 财政年份:
    2009
  • 资助金额:
    $ 37.13万
  • 项目类别:
ATM FUNCTION DURING V(D)J RECOMBINATION
V(D)J 重组期间的 ATM 功能
  • 批准号:
    8271430
  • 财政年份:
    2008
  • 资助金额:
    $ 37.13万
  • 项目类别:
ATM FUNCTION DURING V(D)J RECOMBINATION
V(D)J 重组期间的 ATM 功能
  • 批准号:
    8635819
  • 财政年份:
    2008
  • 资助金额:
    $ 37.13万
  • 项目类别:
ATM FUNCTION DURING V(D)J RECOMBINATION
V(D)J 重组期间的 ATM 功能
  • 批准号:
    8774161
  • 财政年份:
    2008
  • 资助金额:
    $ 37.13万
  • 项目类别:
ATM Function During V(D)J Recombination
V(D)J 重组期间的 ATM 功能
  • 批准号:
    10307563
  • 财政年份:
    2008
  • 资助金额:
    $ 37.13万
  • 项目类别:
ATM FUNCTION DURING V(D)J RECOMBINATION
V(D)J 重组期间的 ATM 功能
  • 批准号:
    10062842
  • 财政年份:
    2008
  • 资助金额:
    $ 37.13万
  • 项目类别:
ATM FUNCTION DURING V(D)J RECOMBINATION
V(D)J 重组期间的 ATM 功能
  • 批准号:
    7742978
  • 财政年份:
    2008
  • 资助金额:
    $ 37.13万
  • 项目类别:
ATM FUNCTION DURING V(D)J RECOMBINATION
V(D)J 重组期间的 ATM 功能
  • 批准号:
    9180672
  • 财政年份:
    2008
  • 资助金额:
    $ 37.13万
  • 项目类别:
ATM FUNCTION DURING V(D)J RECOMBINATION
V(D)J 重组期间的 ATM 功能
  • 批准号:
    8386917
  • 财政年份:
    2008
  • 资助金额:
    $ 37.13万
  • 项目类别:

相似海外基金

Development of back bone vectors for chimeric antigen receptors against key molecules, CD47 and CD24, activating macrophages
开发针对关键分子 CD47 和 CD24 的嵌合抗原受体的骨干载体,激活巨噬细胞
  • 批准号:
    23K06728
  • 财政年份:
    2023
  • 资助金额:
    $ 37.13万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Engineering synthetic adhesion receptors to enhance the sensitivity of therapeutic chimeric antigen receptors
工程合成粘附受体以增强治疗性嵌合抗原受体的敏感性
  • 批准号:
    MR/W031353/1
  • 财政年份:
    2022
  • 资助金额:
    $ 37.13万
  • 项目类别:
    Research Grant
CAREER: Engineering next-generation chimeric antigen receptors for cancer immunotherapy using phospho-proteomics
职业:利用磷酸蛋白质组学设计用于癌症免疫治疗的下一代嵌合抗原受体
  • 批准号:
    2145853
  • 财政年份:
    2022
  • 资助金额:
    $ 37.13万
  • 项目类别:
    Continuing Grant
Construction of a drug discovery platform utilizing antigen receptors that regulate the quality of cancer immunity
利用调节癌症免疫质量的抗原受体构建药物发现平台
  • 批准号:
    22K06603
  • 财政年份:
    2022
  • 资助金额:
    $ 37.13万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Modeling based design of chimeric antigen receptors for Natural Killer cell-based immunotherapy
用于基于自然杀伤细胞的免疫治疗的嵌合抗原受体的基于建模的设计
  • 批准号:
    10701754
  • 财政年份:
    2022
  • 资助金额:
    $ 37.13万
  • 项目类别:
Modeling based design of chimeric antigen receptors for Natural Killer cell-based immunotherapy
用于基于自然杀伤细胞的免疫治疗的嵌合抗原受体的基于建模的设计
  • 批准号:
    10557760
  • 财政年份:
    2022
  • 资助金额:
    $ 37.13万
  • 项目类别:
Molecualr imaging for development of chimeric antigen receptors (CARs) resistant to T cell exhaustion
用于开发抗 T 细胞耗竭的嵌合抗原受体 (CAR) 的分子成像
  • 批准号:
    20H03536
  • 财政年份:
    2020
  • 资助金额:
    $ 37.13万
  • 项目类别:
    Grant-in-Aid for Scientific Research (B)
Chimeric antigen receptors on regulatory T cells as a treatment strategy in auto-immune diseases.
调节性 T 细胞上的嵌合抗原受体作为自身免疫性疾病的治疗策略。
  • 批准号:
    437200
  • 财政年份:
    2020
  • 资助金额:
    $ 37.13万
  • 项目类别:
    Studentship Programs
Therapeutic Anti-HIV Chimeric Antigen Receptors Via Stem Cell Delivery
通过干细胞递送治疗性抗 HIV 嵌合抗原受体
  • 批准号:
    10542442
  • 财政年份:
    2020
  • 资助金额:
    $ 37.13万
  • 项目类别:
Therapeutic Anti-HIV Chimeric Antigen Receptors Via Stem Cell Delivery
通过干细胞递送治疗性抗 HIV 嵌合抗原受体
  • 批准号:
    9922602
  • 财政年份:
    2020
  • 资助金额:
    $ 37.13万
  • 项目类别:
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了