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.

细胞产生一种称为DNA聚合酶的酶，负责“影印”基因组，基因组编码细胞的生物蓝图。聚合酶经常由于DNA损伤或模板上的结构复制引起的遗传障碍而停滞，导致DNA复制缺陷或形成可导致疾病（如癌症）的突变。我们已经确定了一种称为PrimPol的损伤耐受蛋白，其作用是通过重新启动基因组上遇到的障碍下游的DNA合成来重新启动停滞的复制。我们建议确定PrimPol及其合作伙伴如何以及何时定位于停滞复制的位点，这一过程如何受到调节和解除调节，在基因组上，这种重新启动机制发挥作用，最后，PrimPol如何与细胞中的其他重启机制合作，以确保复制以有效的方式进行。了解复制机制如何容忍人类细胞中的这种遗传障碍，将促进开发更有效的抑制剂，阻止癌细胞中的基因组复制。

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