Elucidating how the PrimPol DNA damage tolerance pathway is regulated and where it operates in human cells

阐明 PrimPol DNA 损伤耐受途径的调节方式及其在人体细胞中的作用位置

• 批准号: BB/X000834/1
• 负责人: Aidan Doherty
• 金额: $ 110.67万
• 依托单位: University of Sussex
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FX000834%2F1
• 关键词: Elucidating; how; PrimPol; DNA; damage

Cells produce enzymes called DNA polymerases responsible for "photocopying" the genome, which encodes the cell's biological blueprint. Polymerases are frequently stalled by genetic obstacles caused by DNA damage or structures on the template being replicated, leading to defective DNA copying or the formation of mutations that can lead to diseases, such as cancer. We have identified a damage tolerance protein called PrimPol, whose role it is to restart stalled replication by repriming DNA synthesis downstream of obstacles encountered on the genome. We are proposing to identify how and when PrimPol, and its partners, localise to sites of stalled replication, how this process is regulated and deregulated, where on the genome this repriming mechanism performs its roles and, finally, how PrimPol co-operates with other restart mechanisms in the cell to ensure that replication proceeds in an efficient way. Understanding how the replication machinery tolerates such genetic obstacles in human cells will advance the development of more efficiency inhibitors that block genome duplication in cancer cells.

细胞产生称为DNA聚合酶的酶，负责“影印”基因组，该酶编码细胞的生物蓝图。聚合酶经常被复制的DNA损伤或模板上的结构引起的遗传障碍而停滞，导致DNA复制有缺陷或可能导致疾病（例如癌症）的突变形成。我们已经确定了一种称为PRIMPOL的损伤耐受性蛋白，其作用是通过谴责基因组遇到的障碍物下游的DNA合成来重新启动停滞的复制。我们提议确定Primpol及其何时及其伴侣本地化与停滞的复制站点，如何调节和放松管制，何处在基因组上，这种谴责机制在基因组上扮演其作用，最后，PrimPol合作与细胞中的其他重新启动机制如何确保该复制在有益的方式中进行。了解复制机制如何耐受人类细胞中的这种遗传障碍将推动阻止癌细胞中基因组复制的更多效率抑制剂的发展。

项目成果

Primase-polymerases: how to make a primer from scratch.

• DOI: 10.1042/bsr20221986
• 发表时间: 2023-07-26
• 期刊: Bioscience reports
• 影响因子: 4

Reverse transcriptases prime DNA synthesis.

• DOI: 10.1093/nar/gkad478
• 发表时间: 2023-08-11
• 期刊: Nucleic acids research
• 影响因子: 14.9