Cigarette smoke causes cancer primarily by damaging the DNA. A new study that mapped the DNA damages caused by smoking, reveals that the way our DNA is organized and chemically modified can influence how cigarette smoke damages it, how well the damage is repaired and how many mutations will form. Specifically, areas of DNA that are more open and active are more prone to damage but also better at repairing themselves, which helps to prevent mutations. However, in areas where repair is less efficient, damage can lead to mutations that may drive cancer development This research highlights how our DNA's environment shapes the risk of smoking-related lung cancer. 

The study from The Hebrew University of Jerusalem, led by Prof. Sheera Adar and her graduate student Elisheva Heilbrun-Katz from The Institute for Medical Research Israel-Canada in the Faculty of Medicine in collaboration with Prof. Raluca Gordan from Duke University and the University of Massachusetts, has uncovered how the structure and chemical modifications of DNA affect the damage caused by cigarette smoke and the body’s ability to repair it. This breakthrough helps explain how smoking leads to lung cancer. 

The research focuses on benzo[a]pyrene, a harmful chemical in cigarette smoke. When processed by the body, this chemical becomes Benzo[a]pyrene diol epoxide (BPDE), which can bind to DNA, disrupt its normal function, and lead to cell damage.

Using advanced genomic tools, the researchers discovered that:

DNA’s environment matters: Certain regions of DNA, especially ones that are more open and active, are more prone to damage but are also repaired better by the cells.

Transcription factors can help or harm: Proteins that regulate gene activity can sometimes protect DNA from damage, but in other cases, they make it more vulnerable.

Efficient repair is key: The areas of DNA that are better repaired tend to accumulate fewer mutations, even if they suffered from more damage initially.

The study highlights that the body’s ability to fix DNA damage is more important than the amount of damage when it comes to determining whether mutations will form. These findings provide new insights into how smoking-related mutations occur and may help guide future cancer prevention and treatment strategies.

Funding and Support
This work was generously supported by the Israel Science Foundation (grant 482/22), the Israel Cancer Research Fund (grant 24-102-PG), the US-Israel Binational Science Foundation (grant BSF-2019272), and the Binational Science Foundation-National Science Foundation (grant 2324614). Elisheva Heilbrun is a recipient of the Israel Council for Higher Education Scholarship.  

The research paper titled “The epigenetic landscape shapes smoking-induced mutagenesis by modulating DNA damage susceptibility and repair efficiency” has been published in https://academic.oup.com/nar/article/53/4/gkaf048/8008527?searchresult=1 
https://doi.org/10.1093/nar/gkaf048

Researchers:
Elisheva E. Heilbrun1, Dana Tseitline1, Hana Wasserman2, Ayala Kirshenbaum1, Yuval Cohen1, Raluca Gordan3,4,5 and Sheera Adar1  

Institutions:
1 Department of Microbiology and Molecular Genetics, The Institute for Medical Research Israel-Canada, The Faculty of Medicine, The Hebrew University of Jerusalem
2 Program in Computational Biology and Bioinformatics, Duke University School of Medicine
3 Department of Biostatistics and Bioinformatics, Duke University School of Medicine
4 Department of Computer Science, Duke University
5  Department of Genomics and Computational Biology, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA