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

每个人都暴露在环境中低水平的致癌物质中。苯并苯是一种普遍的污染物，存在于炉子的烟雾中，如木柴燃烧器、废气和烧烤肉类和鱼类。苯并芘是一种遗传毒性诱变剂，这意味着它直接破坏DNA，导致致癌突变。苯并苯很可能会导致肺癌和皮肤癌等常见癌症的发生。苯并吡喃通过其主要活性成分BPDE致癌。BPDE形成称为“加合物”的DNA损伤。BPDE加合物具有很强的突变性，在DNA序列中会引起大小不同的变化或突变。有一些模型可以解释BPDE是如何导致这些突变的，但其中一些途径仍然不清楚。一种称为跨损伤合成的过程被认为是BPDE诱导突变的原因，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(现实生活中经常会出现这种情况)。到底同源重组在DNA中的BPDE加合物上起了什么作用还不是很清楚。我们有新的见解表明，同源重组在BPDE加合物上通过一种不寻常的新机制进行。了解这一新机制有助于解释暴露于苯并(A)芘的一些影响，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。这个项目的目的是用BPDE处理人类细胞系，并使用分子生物学方法，如显微镜，来详细描述新的同源重组途径。这将揭示苯并[2]在细胞中暴露的影响的新见解，这对于理解癌症的环境原因和癌症的一般发展是重要的。

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.