Understanding and targeting RNA/transcription-dependent DNA repair in cancer cells

了解和靶向癌细胞中的 RNA/转录依赖性 DNA 修复

基本信息

  • 批准号:
    10680494
  • 负责人:
  • 金额:
    $ 15.37万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2022
  • 资助国家:
    美国
  • 起止时间:
    2022-09-01 至 2023-12-31
  • 项目状态:
    已结题

项目摘要

Project Summary/Abstract Genomic instability is a hallmark of cancer and is an enabling characteristic of tumorigenesis. Genomic instability can arise from deficiency in DNA repair system. On one hand, deficiency in DNA repair system leads to increased mutation rate in the entire genome, results in genomic instability. On the other hand, deficiency in certain DNA repair pathway(s) may render the cell highly dependent on other repair pathway(s) to cope with high mutation burden, which may constitute a vulnerability that can be exploited for targeted therapies in cancer. Recent success of the PARP inhibitors for treatment of BRCA mutation cancers, has demonstrated great potential to exploit cancer cell-specific dependency on certain DNA repair pathways for cancer therapies. In addition to cancer with BRCA deficiency, multiple researches have suggested to expand PARP inhibitor treatment to cancers with deficiency in homologous recombination (HR) DNA repair pathways. However, our understanding of the HR DNA repair pathways is quite limited. In our recent study on HR DNA repair, we have discovered a novel RNA-dependent HR DNA repair pathway, which is controlled by the DNA repair protein RAD51AP1. The unique ability of RAD51AP1 to promote HR in transcribed regions makes it an attractive target to specifically exacerbate the DNA damage in active genes in cancer cells, especially in cancers driven by oncogenic transcription factors or epigenetic regulators. The amplification and up-regulation of RAD51AP1 in multiple types of cancer have led us to hypothesize that RAD51AP1 may be indispensable in cancer cells with high levels of transcription-driven DNA damage and defects in the canonical HR pathway, which could be exploited for therapeutic interventions. Importantly, the function of RAD51AP1 in promoting HR repair depends on its R-loop formation activity via its DNA/RNA binding motif. This binding interface could potentially provide a targetable site for small molecules to disrupt RAD51AP1 binding to DNA/RNA, which may effectively abolish its R-loop formation activity and results in attenuating its HR DNA repair function in the cell. In summary, we want to expand our mechanistic understanding of the novel RNA/transcription-dependent HR DNA repair pathway, investigate the role of this novel DNA repair in specific types of cancer, ultimately, exploit cancer cell-specific dependency of this pathway for potential cancer therapies.
项目总结/摘要 基因组不稳定性是癌症的标志,也是肿瘤发生的一个有利特征。基因组 不稳定性可由DNA修复系统缺陷引起。一方面,DNA修复系统的缺陷导致 增加整个基因组的突变率,导致基因组不稳定。另一方面, 某些DNA修复途径可能使细胞高度依赖于其他修复途径来科普高水平的损伤。 突变负担,这可能构成可用于癌症靶向治疗的脆弱性。 最近成功的PARP抑制剂治疗BRCA突变癌症,已经证明了巨大的 利用癌细胞对某些DNA修复途径的特异性依赖性进行癌症治疗的潜力。在 除了BRCA缺乏的癌症外,多项研究还建议扩大PARP抑制剂 治疗同源重组(HR)DNA修复途径缺陷的癌症。但我们的 对HR DNA修复途径的了解非常有限。在我们最近对HR DNA修复的研究中,我们 发现了一种新的RNA依赖性HR DNA修复途径,该途径由DNA修复蛋白控制 RAD51AP 1. RAD 51 AP 1在转录区域促进HR的独特能力使其成为有吸引力的靶点 特异性地加剧癌细胞中活性基因的DNA损伤,特别是在由 致癌转录因子或表观遗传调节因子。RAD 51 AP 1基因的扩增和上调在胃癌中的表达 多种类型的癌症使我们假设RAD 51 AP 1可能是癌细胞中不可缺少的, 高水平的转录驱动的DNA损伤和经典HR途径的缺陷,这可能是 用于治疗干预。重要的是,RAD 51 AP 1在促进HR修复中的功能依赖于 通过其DNA/RNA结合基序对其R环形成活性的影响。这个绑定接口可能提供一个 小分子的靶向位点,以破坏RAD 51 AP 1与DNA/RNA的结合,这可以有效地消除其 R环形成活性,并导致其在细胞中的HR DNA修复功能减弱。 总之,我们希望扩大我们对新的RNA/转录依赖的机制的理解。 HR DNA修复途径,研究这种新型DNA修复在特定类型癌症中的作用,最终, 利用该途径的癌细胞特异性依赖性用于潜在的癌症治疗。

项目成果

期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Meiotic protein SYCP2 confers resistance to DNA-damaging agents through R-loop-mediated DNA repair.
减数分裂蛋白 SYCP2 通过 R 环介导的 DNA 修复赋予对 DNA 损伤剂的抵抗力。
  • DOI:
    10.1038/s41467-024-45693-2
  • 发表时间:
    2024
  • 期刊:
  • 影响因子:
    16.6
  • 作者:
    Wang,Yumin;Gao,Boya;Zhang,Luyuan;Wang,Xudong;Zhu,Xiaolan;Yang,Haibo;Zhang,Fengqi;Zhu,Xueping;Zhou,Badi;Yao,Sean;Nagayama,Aiko;Lee,Sanghoon;Ouyang,Jian;Koh,Siang-Boon;Eisenhauer,EricL;Zarrella,Dominique;Lu,Kate;Rueda,Bo
  • 通讯作者:
    Rueda,Bo
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Jian Ouyang其他文献

Jian Ouyang的其他文献

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{{ truncateString('Jian Ouyang', 18)}}的其他基金

Understanding and targeting RNA/transcription-dependent DNA repair in cancer cells
了解和靶向癌细胞中的 RNA/转录依赖性 DNA 修复
  • 批准号:
    10810914
  • 财政年份:
    2022
  • 资助金额:
    $ 15.37万
  • 项目类别:
Understanding and targeting RNA/transcription-dependent DNA repair in cancer cells
了解和靶向癌细胞中的 RNA/转录依赖性 DNA 修复
  • 批准号:
    10516451
  • 财政年份:
    2022
  • 资助金额:
    $ 15.37万
  • 项目类别:

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  • 批准号:
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  • 财政年份:
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  • 资助金额:
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