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: 10680494
• 负责人: Jian Ouyang
• 金额: $ 15.37万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 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
• 来源: https://reporter.nih.gov/project-details/10680494
• 关键词: BRCA deficient; BRCA mutations; Binding; Cells; Characteristics; DNA; DNA Damage; DNA Repair; DNA Repair Gene; DNA Repair Pathway; Defect; Dependence; Epigenetic Process; Genes; Genetic Transcription; Genomic Instability; Malignant Neoplasms; Mutation; Oncogenic; Pathway interactions; Poly(ADP-ribose) Polymerase Inhibitor; Predisposition; RNA; RNA Binding; Research; Role; Site; System; Therapeutic; Therapeutic Intervention; Up-Regulation; cancer cell; cancer therapy; cancer type; coping; homologous recombination; novel; recombinational repair; repair function; repaired; small molecule; success; targeted treatment; transcription factor; tumorigenesis; whole genome

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.

项目摘要/摘要 基因组不稳定性是癌症的标志，并且是肿瘤发生的有效特征。基因组 DNA修复系统缺乏可能会引起不稳定性。一方面，DNA修复系统的缺陷导线 为了提高整个基因组的突变率，导致基因组不稳定性。另一方面，缺乏 某些DNA修复途径可能会使细胞高度依赖于其他修复途径以应对高 突变负担可能构成一个脆弱性，可用于癌症的靶向疗法。 PARP抑制剂在治疗BRCA突变癌的最新成功表现出了很大的表现 利用对癌症疗法某些DNA修复途径的癌细胞特异性依赖性的潜力。在 除了BRCA缺乏症外，还建议扩大PARP抑制剂 对同源重组（HR）DNA修复途径缺乏的癌症的治疗。但是，我们的 对HR DNA修复途径的了解非常有限。在我们最近关于HR DNA修复的研究中，我们有 发现了一种新型的RNA依赖性HR DNA修复途径，该途径由DNA修复蛋白控制 RAD51AP1。 RAD51AP1在转录区域促进人力资源的独特能力使其成为有吸引力的目标 特别加剧了癌细胞中活性基因中的DNA损伤，尤其是在癌症中 致癌转录因子或表观遗传调节剂。 RAD51AP1的扩增和上调 多种类型的癌症使我们假设Rad51ap1在具有的癌细胞中可能是必不可少的 高水平的转录驱动的DNA损伤和规范HR途径中的缺陷，这可能是 用于治疗干预措施。重要的是，rad51ap1在促进HR修复中的功能取决于 通过其通过其DNA/RNA结合基序的R环形成活性。该绑定界面可能会提供 小分子的目标位点破坏Rad51ap1与DNA/RNA的结合，这可能有效废除其 R环的形成活性并导致细胞中其HR DNA修复功能减弱。 总而言之，我们希望扩展我们对新型RNA/转录依赖性的机械理解 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 利用该途径对潜在癌症疗法的癌细胞特异性依赖性。

项目成果

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: Nature communications
• 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