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

点击翻译按钮获取中文摘要

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.