Characterising novel recombination pathways at DNA adducts of the environmental mutagen BPDE

环境诱变剂 BPDE 的 DNA 加合物的新型重组途径的表征

• 批准号: MR/S021310/1
• 负责人: Eva Petermann
• 金额: $ 46.49万
• 依托单位: University of Birmingham
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2019
• 资助国家: 英国
• 起止时间: 2019 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FS021310%2F1
• 关键词: Characterising; novel; recombination; pathways; DNA

Everyone is exposed to low levels of cancer-causing agents in the environment. Benzopyrene is a general pollutant that is found in smoke from stoves such as woodburners, exhaust fumes and barbequed meat and fish. Benzopyrene is a genotoxic mutagen, meaning that it directly damages the DNA to cause cancer-promoting mutations. It is likely that benzopyrene contributes to the development of common cancers such as lung and skin cancer. Benzopyrene causes cancer through its main active ingredient, which is called BPDE. BPDE forms DNA damages called "adducts". BPDE adducts are very mutagenic, and cause both small and large changes, or mutations, in the DNA sequence. There are models explaining how BPDE causes these mutations, but some of the pathways are still not understood. A process called translesion synthesis has been made responsible for BPDE-induced mutations, but there is a lot of evidence that another pathway called homologous recombination is also involved. Homologous recombination may sometimes be more important, especially if BPDE levels in the DNA are low (which will often be the case in real life). What exactly homologous recombination does at BPDE adducts in the DNA is not very well understood.We have new insights showing that homologous recombination proceeds by an unusual new mechanism at BPDE adducts. Understanding this new mechanism could help explain some of the effects of benzopyrene exposure, which could help to better predict and detect negative effects of pollution. It could also help predict which individuals will be more sensitive to carcinogen exposure. The aim of this project is to treat human cell lines with BPDE and use molecular biology methods, such as microscopy, to characterise the new homologous recombination pathway in detail. This will reveal new insights into the effects of benzopyrene exposure in the cells, which is important for understanding environmental causes of cancer and cancer development in general.

每个人都会接触环境中低含量的致癌物质。苯并芘是一种常见污染物，存在于燃木炉等炉灶的烟雾、废气以及烤肉和烤鱼中。苯并芘是一种基因毒性诱变剂，这意味着它会直接损害 DNA，导致致癌突变。苯并芘可能会导致肺癌和皮肤癌等常见癌症的发生。苯并芘通过其主要活性成分（称为 BPDE）致癌。 BPDE 形成称为“加合物”的 DNA 损伤。 BPDE 加合物具有很强的诱变性，会导致 DNA 序列发生大大小小的变化或突变。有一些模型可以解释 BPDE 如何导致这些突变，但其中一些途径仍不清楚。 BPDE 诱导的突变由一种称为跨损伤合成的过程负责，但有大量证据表明，另一种称为同源重组的途径也参与其中。同源重组有时可能更重要，特别是当 DNA 中的 BPDE 水平较低时（现实生活中经常出现这种情况）。同源重组在 DNA 中的 BPDE 加合物中的具体作用尚不清楚。我们有新的见解表明，同源重组通过 BPDE 加合物中一种不寻常的新机制进行。了解这种新机制有助于解释苯并芘暴露的一些影响，从而有助于更好地预测和检测污染的负面影响。它还可以帮助预测哪些人对致癌物暴露更敏感。该项目的目的是用 BPDE 处理人类细胞系，并使用分子生物学方法（例如显微镜）来详细表征新的同源重组途径。这将揭示苯并芘暴露对细胞影响的新见解，这对于了解癌症的环境原因和癌症发展非常重要。

项目成果

Conflicts with transcription make early replication late.

• DOI: 10.1016/j.molcel.2022.08.026
• 发表时间: 2022-09
• 期刊: Molecular cell
• 影响因子: 16
• 作者: E. Petermann

PrimPol-dependent single-stranded gap formation mediates homologous recombination at bulky DNA adducts.

• DOI: 10.1038/s41467-020-19570-7
• 发表时间: 2020-11-17
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Piberger AL;Bowry A;Kelly RDW;Walker AK;González-Acosta D;Bailey LJ;Doherty AJ;Méndez J;Morris JR;Bryant HE;Petermann E
• 通讯作者: Petermann E