Metnase, PIKK, and RPA Roles in DNA Damage and Replication Stress Responses

Metnase、PIKK 和 RPA 在 DNA 损伤和复制应激反应中的作用

基本信息

  • 批准号:
    9100800
  • 负责人:
  • 金额:
    $ 27.04万
  • 依托单位:
  • 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:
    2009-02-01 至 2017-06-30
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Most cancer patients receive radio- and/or chemotherapy that causes DNA damage, which blocks DNA replication. Normal and tumor cells respond to DNA damage and associated replication stress by activating DNA repair, cell cycle arrest (checkpoint) systems, and when damage is severe, programmed death pathways, collectively termed the DNA damage response (DDR). DDR proteins play crucial roles in tumor suppression and genome stabilization (cancer etiology) as well as tumor response to radio- and chemotherapy (cancer treatment). DDR pathways determine cell fates in response to DNA damage, including cell survival, genome stability, and cell death/permanent growth arrest via apoptosis, autophagy, necrosis, senescence, or mitotic catastrophe. Cells are particularly vulnerable to DNA damage during S phase because most DNA lesions stall replication forks, causing replication stress. This proposal focuses on several proteins with roles in DNA repair, checkpoint activation, and recovery from replication stress. Metnase and DNA-PK were both initially characterized for their roles in DNA double-strand break (DSB) repair by non-homologous end joining (NHEJ). Recent studies demonstrate that Metnase and DNA-PK (along with replication protein A (RPA), ATM/ATR, Chk1, and others) also function in checkpoint activation and replication stress recovery. The replication checkpoint prevents new origin firing and stabilizes stalled replication forks to prevent fork collapse, allowing time for repair and for restart. Persistent replication stress can lead to fork collapse, producing one-ended DSBs marked by phosphorylated H2AX (γ-H2AX). RPA accumulates on single-stranded DNA at stalled forks and the RPA32 subunit is phosphorylated at multiple sites by phosphoinositide 3-kinase-related protein kinases (PIKKs) DNA-PK, ATM and ATR, leading to Chk1 activation and replication arrest. Metnase also regulates Chk1 activation and replication arrest. Our central hypothesis is that Metnase, DNA-PK, and RPA operate within the DDR to influence cell fate after genotoxic stress, including cell survival, genome stability, and death pathway activation. We will determine roles of Metnase (Aim 1) and PIKK phosphorylation of RPA (Aim 2) in replication stress responses including replication arrest, fork restart, genome stability, cell survival and cell death by apoptosis. In Aim 3 we will define epistatic relationships between Metnase and PIKK/RPA pathways, and test novel combinations of replication stress agents plus DDR inhibitors to enhance killing of breast, lung, pancreatic, colon, head and neck, and leukemic tumor cells. A better understanding of how DDR factors regulate cell fate decisions will drive the development of novel cancer therapies to improve local tumor control, and reduce the risk of therapy-induced tumor progression and secondary tumor induction.
描述(由申请人提供):大多数癌症患者接受放疗和/或化疗,导致DNA损伤,从而阻止DNA复制。正常和肿瘤细胞通过激活DNA修复、细胞周期阻滞(检查点)系统以及当损伤严重时的程序性死亡途径(统称为DNA损伤反应(DDR))来响应DNA损伤和相关的复制应激。DDR蛋白在肿瘤抑制和基因组稳定(癌症病因学)以及肿瘤对放疗和化疗(癌症治疗)的反应中起着至关重要的作用。DDR途径决定细胞对DNA损伤的反应,包括细胞存活、基因组稳定性和细胞死亡/通过凋亡、自噬、坏死、衰老或有丝分裂灾难的永久生长停滞。细胞在S期特别容易受到DNA损伤,因为大多数DNA损伤使复制叉停滞,导致复制应激。该提案侧重于在DNA修复,检查点激活和复制应激恢复中发挥作用的几种蛋白质。Metnase和DNA-PK最初都是通过非同源末端连接(NHEJ)在DNA双链断裂(DSB)修复中发挥作用。最近的研究表明,Metnase和DNA-PK(沿着复制蛋白A(RPA)、ATM/ATR、Chk 1等)也在检查点激活和复制应激恢复中起作用。复制检查点可防止新的原点触发,并稳定停滞的复制分叉以防止分叉崩溃,从而留出时间进行修复和重新启动。持续的复制应激可导致分叉崩溃,产生以磷酸化标记的单端DSB。 H2AX(γ-H2AX)。RPA在停滞分叉处的单链DNA上积累,RPA 32亚基在多个位点被磷酸肌醇3-激酶相关蛋白激酶(PIKK)DNA-PK、ATM和ATR磷酸化,导致Chk 1激活和复制停滞。Metnase还调节Chk 1激活和复制停滞。我们的中心假设是,Metnase,DNA-PK和RPA在DDR内操作,以影响基因毒性应激后的细胞命运,包括细胞存活,基因组稳定性和死亡途径激活。我们将确定Metnase(Aim 1)和RPA(Aim 2)的PIKK磷酸化在复制应激反应中的作用,包括复制停滞,叉重新启动,基因组稳定性,细胞存活和细胞凋亡引起的细胞死亡。在目标3中,我们将定义Metnase和PIKK/RPA途径之间的上位关系,并测试复制应激剂加DDR抑制剂的新型组合,以增强对乳腺、肺、胰腺、结肠、头颈部和白血病肿瘤细胞的杀伤。更好地了解DDR因子如何调节细胞命运决定将推动新型癌症疗法的开发,以改善局部肿瘤控制,并降低治疗诱导的肿瘤进展和继发性肿瘤诱导的风险。

项目成果

期刊论文数量(17)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
FOXF1 mediates mesenchymal stem cell fusion-induced reprogramming of lung cancer cells.
  • DOI:
    10.18632/oncotarget.2413
  • 发表时间:
    2014-10-15
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Wei HJ;Nickoloff JA;Chen WH;Liu HY;Lo WC;Chang YT;Yang PC;Wu CW;Williams DF;Gelovani JG;Deng WP
  • 通讯作者:
    Deng WP
Assaying DNA double-strand break induction and repair as fast as a speeding comet.
  • DOI:
    10.4161/cc.24667
  • 发表时间:
    2013-05-01
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Nickoloff JA
  • 通讯作者:
    Nickoloff JA
Improving cancer therapy by combining cell biological, physical, and molecular targeting strategies.
通过结合细胞生物学、物理和分子靶向策略来改善癌症治疗。
Roles of homologous recombination in response to ionizing radiation-induced DNA damage.
The DNA repair component Metnase regulates Chk1 stability.
DNA 修复成分 Metnase 调节 Chk1 稳定性。
  • DOI:
    10.1186/1747-1028-9-1
  • 发表时间:
    2014
  • 期刊:
  • 影响因子:
    2.3
  • 作者:
    Williamson,ElizabethA;Wu,Yuehan;Singh,Sudha;Byrne,Michael;Wray,Justin;Lee,Suk-Hee;Nickoloff,JacA;Hromas,Robert
  • 通讯作者:
    Hromas,Robert
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Jac A Nickoloff其他文献

Regulation of DNA double-strand break repair pathway choice
DNA 双链断裂修复途径选择的调控
  • DOI:
    10.1038/cr.2007.111
  • 发表时间:
    2007-12-24
  • 期刊:
  • 影响因子:
    25.900
  • 作者:
    Meena Shrivastav;Leyma P De Haro;Jac A Nickoloff
  • 通讯作者:
    Jac A Nickoloff

Jac A Nickoloff的其他文献

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{{ truncateString('Jac A Nickoloff', 18)}}的其他基金

METNASE ROLES IN NHEJ, DNA INTEGRATION AND TRANSLOCATION
METNASE 在 NHEJ、DNA 整合和易位中的作用
  • 批准号:
    8007529
  • 财政年份:
    2010
  • 资助金额:
    $ 27.04万
  • 项目类别:
METNASE ROLES IN NHEJ, DNA INTEGRATION AND TRANSLOCATION
METNASE 在 NHEJ、DNA 整合和易位中的作用
  • 批准号:
    7760561
  • 财政年份:
    2009
  • 资助金额:
    $ 27.04万
  • 项目类别:
METNASE ROLES IN NHEJ, DNA INTEGRATION AND TRANSLOCATION
METNASE 在 NHEJ、DNA 整合和易位中的作用
  • 批准号:
    8213573
  • 财政年份:
    2009
  • 资助金额:
    $ 27.04万
  • 项目类别:
METNASE ROLES IN NHEJ, DNA INTEGRATION AND TRANSLOCATION
METNASE 在 NHEJ、DNA 整合和易位中的作用
  • 批准号:
    8022920
  • 财政年份:
    2009
  • 资助金额:
    $ 27.04万
  • 项目类别:
Metnase, PIKK, and RPA Roles in DNA Damage and Replication Stress Responses
Metnase、PIKK 和 RPA 在 DNA 损伤和复制应激反应中的作用
  • 批准号:
    8584920
  • 财政年份:
    2009
  • 资助金额:
    $ 27.04万
  • 项目类别:
MAMMALIAN DOUBLE-STRAND BREAK AND RECOMBINATIONAL REPAIR
哺乳动物双链断裂和重组修复
  • 批准号:
    7123263
  • 财政年份:
    2005
  • 资助金额:
    $ 27.04万
  • 项目类别:
DSB REPAIR RECOMBINATION, AND GENOME STABILITY
DSB 修复重组和基因组稳定性
  • 批准号:
    7024492
  • 财政年份:
    2004
  • 资助金额:
    $ 27.04万
  • 项目类别:
DSB REPAIR RECOMBINATION, AND GENOME STABILITY
DSB 修复重组和基因组稳定性
  • 批准号:
    6727092
  • 财政年份:
    2004
  • 资助金额:
    $ 27.04万
  • 项目类别:
DSB REPAIR RECOMBINATION, AND GENOME STABILITY
DSB 修复重组和基因组稳定性
  • 批准号:
    6874378
  • 财政年份:
    2004
  • 资助金额:
    $ 27.04万
  • 项目类别:
DSB REPAIR RECOMBINATION, AND GENOME STABILITY
DSB 修复重组和基因组稳定性
  • 批准号:
    7198028
  • 财政年份:
    2004
  • 资助金额:
    $ 27.04万
  • 项目类别:
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